Talk:Β-Hydroxy β-methylbutyric acid

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A fact from this article appeared on Wikipedia's Main Page in the "Did you know?" column on January 22, 2018. The text of the entry was: Did you know ... that in healthy adults, HMB has been shown to increase exercise-induced gains in muscle size, muscle strength, and lean body mass, reduce muscle damage, and speed recovery from exercise?
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Most of these articles are currently available here. The file names reflect the ref names defined in the source code below. Seppi333 (Insert 2¢) 19:05, 23 May 2016 (UTC)[reply]

February 2013 review, indicates the impracticality of obtaining a 3 gram dose through diet^[1]
Skeletal muscle homeostasis, 2016 review^[2] (Available for free at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843955/)
July 2010 review of various HMB-induced biomarker changes/athletic effects^[3]
Medical use in sarcopenia, November 2014 systematic review^[4]
Tentatively supports a more general statement about attentuating muscle damage in pathological states, December 2013 systematic review^[5]
Supplementation in older adults, September 2015 meta-analytic systematic review^[6]
Prevalence of use, pharmacodynamics, availability, and sports testing status, April 2015 performance-enhancing drugs review^[7]
Newest review on HMB: medical use in muscle wasting and sarcopenia, April 2016 review^[8]
Athletic performance-related effects of HMB, 2011 review^[9]
HMB for cancer cachexia, 2013 review^[10]
Effects of amino acid derivatives, 2015 review^[11]
Review with background info on molecular signaling cascades in protein synthesis/degradation, September 2015 review^[12]
HMB's clinical evidence in older adults, May 2016 review^[13] (Available for free at http://www.mdpi.com/2072-6643/8/5/295/htm)
Nutrition supplements for athletes, February 2014 review^[14]
HMDB entry^[15]
Sarcopenia, July 2015 review^[16]
HMB's in vivo intracellular pharmacodynamics in human skeletal muscle, 2013 primary study using muscle biopsies^[17] - cited by ^[2]^[6]^[16]
HMB in animals, June 2015 review,^[18]
Sarcopenia, May 2016 review^[19]
Very strong statements of efficacy for medical use, June 2016 review;^[20] (note: this review explicitly states that HMB ingestion can improve every core symptom of sarcopenia and other forms of muscle wasting: the loss of muscle mass, function, and strength):
This review supports the following statements:
- HMB is a potent stimulator of MPS and a potent inhibitor of MPB.^[20]
- HMB potently inhibits and may reverse muscle loss in sarcopenic individuals and even in hypercatabolic disease states such as cachexia.^[20]
- Ingestion of HMB results in demonstrable muscle mass accretion.^[20]
- Ingestion of HMB can improve measures of muscle strength in sarcopenic individuals.^[20]
- Consumption of HMB with dietary protein can improve muscle function, resulting in functional muscle performance improvements.^[20]
- The overall treatment of muscle wasting conditions should include dietary supplementation with HMB.^[20]
- Ingestion of HMB and consumption of a high protein diet combined with regular resistance exercise is recommended for individuals that are at risk of developing or currently experiencing sarcopenia.^[20]
July 2014 review;^[21] Covers trials involving Juven for various medical conditions w/ positive (AIDS-induced wasting, cancer cachexia) and negative findings (post-gastric bypass, rheumatoid arthritis) and an interesting trial involving Juven vs HMB alone vs placebo, where HMB alone significantly improved nitrogen balance relative to Juven or placebo.

References

^ ^a ^b ^c ^d ^e Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". J. Int. Soc. Sports. Nutr. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064. PMID 23374455. The International Society of Sports Nutrition (ISSN) bases the following position stand on a critical analysis of the literature on the use of beta-hydroxy-beta-methylbutyrate (HMB) as a nutritional supplement. The ISSN has concluded the following. 1. HMB can be used to enhance recovery by attenuating exercise induced skeletal muscle damage in trained and untrained populations. 2. If consuming HMB, an athlete will benefit from consuming the supplement in close proximity to their workout. 3. HMB appears to be most effective when consumed for 2 weeks prior to an exercise bout. 4. Thirty-eight mg·kg·BM-1 daily of HMB has been demonstrated to enhance skeletal muscle hypertrophy, strength, and power in untrained and trained populations when the appropriate exercise prescription is utilized. 5. Currently, two forms of HMB have been used: Calcium HMB (HMB-Ca) and a free acid form of HMB (HMB-FA). HMB-FA may increase plasma absorption and retention of HMB to a greater extent than HMB-CA. However, research with HMB-FA is in its infancy, and there is not enough research to support whether one form is superior. 6. HMB has been demonstrated to increase LBM and functionality in elderly, sedentary populations. 7. HMB ingestion in conjunction with a structured exercise program may result in greater declines in fat mass (FM). 8. HMB's mechanisms of action include an inhibition and increase of proteolysis and protein synthesis, respectively. 9. Chronic consumption of HMB is safe in both young and old populations. ... HMB is naturally produced in animals and humans from the amino acid leucine [27]. The first step in production of HMB is the reversible transamination of leucine to α-keto-isocaproate (KIC) by the enzyme branched chain amino acid transferase [28] ... KIC is primarily metabolized into isovaleryl-CoA, with only approximately 5% of leucine being converted into HMB [28]. To put this into perspective, an individual would need to consume over 600 g of high quality protein to obtain the amount of leucine (60 grams) necessary to produce the typical 3 g daily dosage of HMB used in human studies [9]. Since consumption of this amount of protein is impractical, HMB is typically increased via dietary supplementation.
^ ^a ^b ^c Brook MS, Wilkinson DJ, Phillips BE, Perez-Schindler J, Philp A, Smith K, Atherton PJ (January 2016). "Skeletal muscle homeostasis and plasticity in youth and ageing: impact of nutrition and exercise". Acta Physiol (Oxf). 216 (1): 15–41. doi:10.1111/apha.12532. PMC 4843955. PMID 26010896. The mechanisms regulating loss of skeletal muscle mass with age still remain unclear; however, with the shrinkage of any organ (other than necrosis), they must be due to chronic imbalances between protein synthesis (MPS) and protein breakdown (MPB), that is MPB > MPS. ... Therefore, in the post‐absorptive state, rates of MPB > MPS leading to a net negative protein balance and hence a loss of muscle protein. Crucially, this negative protein balance is transiently reversed (MPS > MPB) after food intake (contingent on sufficient high‐quality protein), such that net protein balance is neutral on a daily basis (MPS = MPB). The mechanisms underlying the anabolic effects of food intake involve both the stimulation of MPS (Rennie et al. 1982) and suppression of MPB (Wilkes et al. 2009). The potent increase in MPS is driven almost entirely by essential amino acids (EAAs) (Smith et al. 1992), with the branched chain AA (BCAA: leucine, isoleucine and valine), in particular leucine [and its metabolite(s), e.g. β‐hydroxy β‐methylbutyric acid (HMB) (Van Koevering & Nissen 1992)] being central to these effects (Wilkinson et al. 2013). ... Despite extensive investment in pharmaceutical interventions (Onder et al. 2009) and the discovery of a number of potential novel targeted pharmaconutrients [ursolic acid (UA), HMB, PA, etc. (Vukovich et al. 2001, Kunkel et al. 2011, Hoffman et al. 2012)], RE with appropriate supportive nutrition remains the current most effective and safe means by which to maintain or increase muscle mass in older adults (Ivey et al. 2000, Parise & Yarasheski 2000, Häkkinen et al. 2001, Kumar et al. 2012). ... More recent studies have shown that some nutritional supplements such as the leucine metabolite HMB, which is known to have potent affects on both MPS and MPB (Wilkinson et al. 2013), have potential to prevent or slow the decline in bed rest‐related muscle loss (Deutz et al. 2013), indicating the importance of nutritional strategies for assisting in combating the accelerated mass loss (Magne et al. 2013).
^ Portal S, Eliakim A, Nemet D, Halevy O, Zadik Z (July 2010). "Effect of HMB supplementation on body composition, fitness, hormonal profile and muscle damage indices". J. Pediatr. Endocrinol. Metab. 23 (7): 641–50. doi:10.1515/jpem.2010.23.7.641. PMID 20857835. S2CID 2209268. There is a huge market for ergogenic supplements for athletes. However, only a few products have been proven to have ergogenic effects and to be effective at improving muscle strength and body composition. One such supplement is beta-hydroxy beta-methylbutyrate (HMB). ... Several studies have shown that combining exercise training with HMB supplementation leads to increased muscle mass and strength, and there is some anecdotal evidence of aerobic improvement. However, HMB supplementation has been found to be effective mainly for untrained individuals. While previous reviews have emphasized three main pathways for HMB's mode of action: 1) enhancement of sarcolemmal integrity via cytosolic cholesterol, 2) inhibition of protein degradation via proteasomes, and 3) increased protein synthesis via the mTOR pathway, more recent studies have suggested additional possible mechanisms for its physiological effects. These include decreased cell apoptosis and enhanced cell survival, increased proliferation, differentiation and fusion via the MAPK/ERK and PI3K/Akt pathways, and enhanced IGF-I transcription.
^ Cruz-Jentoft AJ, Landi F, Schneider SM, Zúñiga C, Arai H, Boirie Y, Chen LK, Fielding RA, Martin FC, Michel JP, Sieber C, Stout JR, Studenski SA, Vellas B, Woo J, Zamboni M, Cederholm T (November 2014). "Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS)". Age Ageing. 43 (6): 748–59. doi:10.1093/ageing/afu115. PMC 4204661. PMID 25241753. Essential amino acid (EAA) supplements, including ∼2.5 g of leucine, and β-hydroxy β-methylbutyric acid (HMB) supplements, show some effects in improving muscle mass and function parameters. Protein supplements have not shown consistent benefits on muscle mass and function. ... Supervised resistance exercise is recommended for individuals with sarcopenia. EAA (with leucine) and HMB may improve muscle outcomes. ...
HMB supplementation
The effect of HMB alone [32, 36] or HMB in combination with ARG and LYS [34] or resistance exercise training [39] on muscle parameters has been investigated in four high-quality (PEDro score: 8–10) studies of 8–24-week duration in community-dwelling older adults [34, 36, 39] or in healthy older adults on extended bed rest [32]. HMB prevented muscle mass loss in one of four studies and did not improve muscle mass in the other three [32]; improved muscle strength in one [34] (and possibly two) [36] of four studies and improved physical performance in one of four studies [34].
Overall, HMB showed some effects on muscle mass and function in these high-quality studies, but sample sizes were small.
^ Molfino A, Gioia G, Rossi Fanelli F, Muscaritoli M (December 2013). "Beta-hydroxy-beta-methylbutyrate supplementation in health and disease: a systematic review of randomized trials". Amino Acids. 45 (6): 1273–1292. doi:10.1007/s00726-013-1592-z. PMID 24057808. Beta-hydroxy-beta-methylbutyrate (HMB), a metabolite of the branched-chain amino acid leucine, is extensively used by athletes and bodybuilders in order to increase strength, muscle mass and exercise performance. ... The indexed studies support that HMB is effective in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases. Most of the selected studies showed the effectiveness of HMB in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases. The usual dose of 3 g/day may be routinely recommended to maintain or improve muscle mass and function in health and disease. The safety profile of HMB is unequivocal. Further, well-designed clinical studies are needed to confirm effectiveness and mode of action of HMB, particularly in pathological conditions.
^ ^a ^b Wu H, Xia Y, Jiang J, Du H, Guo X, Liu X, Li C, Huang G, Niu K (September 2015). "Effect of beta-hydroxy-beta-methylbutyrate supplementation on muscle loss in older adults: a systematic review and meta-analysis". Arch. Gerontol. Geriatr. 61 (2): 168–175. doi:10.1016/j.archger.2015.06.020. PMID 26169182. RESULTS: A total of seven randomized controlled trials were included, in which 147 older adults received HMB intervention and 140 were assigned to control groups. The meta-analysis showed greater muscle mass gain in the intervention groups compared with the control groups (standard mean difference=0.352kg; 95% confidence interval: 0.11, 0.594; Z value=2.85; P=0.004). There were no significant fat mass changes between intervention and control groups (standard mean difference=-0.08kg; 95% confidence interval: -0.32, 0.159; Z value=0.66; P=0.511).
CONCLUSION: Beta-hydroxy-beta-methylbutyrate supplementation contributed to preservation of muscle mass in older adults. HMB supplementation may be useful in the prevention of muscle atrophy induced by bed rest or other factors. Further studies are needed to determine the precise effects of HMB on muscle strength and physical function in older adults.
^ Momaya A, Fawal M, Estes R (April 2015). "Performance-enhancing substances in sports: a review of the literature". Sports Med. 45 (4): 517–531. doi:10.1007/s40279-015-0308-9. PMID 25663250. S2CID 45124293.
3.6 Beta-Hydroxy-Beta-Methylbutyrate
HMB is a metabolite of the amino acid leucine and is a precursor to cholesterol. ... A 2013 NCAA survey study reported a 0.2 % rate of use among all student athletes [13]. However, it appears that HMB is increasingly being added to many training regimens [88]. ... There are several proposed mechanisms by which HMB acts. One of the primary mechanisms involves the up-regulation of the mechanistic target of rapamycin/ p70S6K signaling pathway, which promotes protein synthesis and muscle hypertrophy [89].
Other studies have focused on the anti-catabolic effects of HMB. Smith et al. [90] demonstrated that HMB preserved lean body mass and decreased proteolysis through the down-regulation of the increased expression of certain components of the ubiquitin–proteasome proteolytic pathway. Some studies have examined HMB and its effect on muscle by measuring markers of muscle breakdown. Wilson et al. [91] demonstrated that when non-resistance trained males received HMB pre-exercise, the rise of lactate dehydrogenase (LDH) levels reduced, and HMB tended to decrease soreness. Knitter et al. [92] showed a decrease in LDH and creatine phosphokinase (CPK), a byproduct of muscle breakdown, by HMB after a prolonged run. ... Despite differences in these studies, it does appear that HMB overall enhances muscular hypertrophy, strength, and power. In fact, the International Society for Sports Nutrition, in a position statement, writes that HMB can be used to enhance recovery by reducing skeletal muscle damage after exercise in athletically trained and untrained people. The utility of HMB does seem to be affected by timing of intake prior to workouts and dosage [97]. Further, chronic consumption of HMB appears safe [97]. ... Currently, HMB is available as an over-the-counter supplement. The drug is not tested for nor banned by any sporting organization.
^ Brioche T, Pagano AF, Py G, Chopard A (April 2016). "Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention" (PDF). Mol. Aspects Med. 50: 56–87. doi:10.1016/j.mam.2016.04.006. PMID 27106402. S2CID 29717535. In conclusion, HMB treatment clearly appears to be a safe potent strategy against sarcopenia, and more generally against muscle wasting, because HMB improves muscle mass, muscle strength, and physical performance. It seems that HMB is able to act on three of the four major mechanisms involved in muscle deconditioning (protein turnover, apoptosis, and the regenerative process), whereas it is hypothesized to strongly affect the fourth (mitochondrial dynamics and functions). Moreover, HMB is cheap (~30–50 US dollars per month at 3 g per day) and may prevent osteopenia (Bruckbauer and Zemel, 2013; Tatara, 2009; Tatara et al., 2007, 2008, 2012) and decrease cardiovascular risks (Nissen et al., 2000). For all these reasons, HMB should be routinely used in muscle-wasting conditions especially in aged people.
^ Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (April 2011). "HMB supplementation: clinical and athletic performance-related effects and mechanisms of action". Amino Acids. 40 (4): 1015–1025. doi:10.1007/s00726-010-0678-0. PMID 20607321. S2CID 11120110.
^ Kim JS, Khamoui AV, Jo E, Park BS, Lee WJ (October 2013). "β-Hydroxy-β-methylbutyrate as a countermeasure for cancer cachexia: a cellular and molecular rationale". Anticancer Agents Med. Chem. 13 (8): 1188–1196. doi:10.2174/18715206113139990321. PMID 23919746.
^ Luckose F, Pandey MC, Radhakrishna K (2015). "Effects of amino acid derivatives on physical, mental, and physiological activities". Crit. Rev. Food Sci. Nutr. 55 (13): 1793–1807. doi:10.1080/10408398.2012.708368. PMID 24279396. S2CID 22657268. Creatine, carnitine, HMB, and taurine are reported to delay the onset of fatigue, improve exercise performance, and body strength. HMB helps in increasing fat-free mass and reduce exercise induced muscle injury. ... [Need full text for more detail]
^ Dutt V, Gupta S, Dabur R, Injeti E, Mittal A (September 2015). "Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action". Pharmacol. Res. 99: 86–100. doi:10.1016/j.phrs.2015.05.010. PMID 26048279.
^ Landi F, Calvani R, Tosato M, Martone AM, Ortolani E, Savera G, D'Angelo E, Sisto A, Marzetti E (May 2016). "Protein Intake and Muscle Health in Old Age: From Biological Plausibility to Clinical Evidence". Nutrients. 8 (5): 295. doi:10.3390/nu8050295. PMC 4882708. PMID 27187465. Given the role of leucine as the master dietary regulator of muscle protein turnover, the ingestion of protein sources enriched with this essential amino acid, or its metabolite β-hydroxy β-methylbutyrate, is thought to offer the greatest benefit in terms of preservation of muscle mass and function in old age. ... Recently, it has been demonstrated that β-hydroxy β-methylbutyrate (HMB)—an amino acid metabolite of leucine—is able to stimulate protein synthesis and improve muscle strength and body composition in older adults [67]. ...
6.2. Nutritional Supplementation with HMB
HMB is an active leucine metabolite which activates the mTOR signaling pathway in muscle. Following its absorption, dietary leucine is converted into α-ketoisocaproate (KIC), which is further metabolized into either isovaleryl-CoA or HMB. Under normal conditions, the majority of KIC is converted into isovaleryl-CoA, while only approximately 5% of leucine is metabolized to HMB. This implies that, in order to reach pharmacological levels of HMB, this compound needs to be administered directly, rather than via increasing leucine dosage. It has recently been suggested that HMB may be used to protect or restore muscle mass in older persons with reduced lean body mass [74].
HMB exerts its effects through protective, anticatabolic mechanisms and directly influences protein synthesis. HMB has also been shown to stabilize the muscle cell membrane, to modulate protein degradation and to up-regulate protein synthesis [68]. The daily administration of a nutritional mixture including HMB (2 g), arginine (5 g), and lysine (1.5 g) for 12 weeks was shown to improve physical performance, muscle strength, fat-free mass and protein synthesis in sedentary older women [74]. More recently, Deutz and colleagues [13]—in a multicenter, randomized, placebo-controlled, double-blind trial—demonstrated that the early administration (within 72 h of hospitalization) of a nutrient-dense oral nutritional supplement containing high concentrations of protein and HMB was associated with decreased post-discharge mortality and improved nutritional status in malnourished older adults [13].
^ Mullin GE (February 2014). "Nutrition supplements for athletes: potential application to malnutrition". Nutr. Clin. Pract. 29 (1): 146–147. doi:10.1177/0884533613516130. PMID 24336486.
^ "3-Hydroxyisovaleric acid". Human Metabolome Database. 11 February 2016. Retrieved 25 May 2016.
^ ^a ^b Phillips SM (July 2015). "Nutritional supplements in support of resistance exercise to counter age-related sarcopenia". Adv. Nutr. 6 (4): 452–460. doi:10.3945/an.115.008367. PMC 4496741. PMID 26178029.
^ Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ, Atherton PJ (June 2013). "Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism" (PDF). J. Physiol. (Lond.). 591 (11): 2911–2923. doi:10.1113/jphysiol.2013.253203. PMC 3690694. PMID 23551944. Retrieved 27 May 2016.
^ Szcześniak KA, Ostaszewski P, Fuller JC, Ciecierska A, Sadkowski T (June 2015). "Dietary supplementation of β-hydroxy-β-methylbutyrate in animals - a review". J Anim Physiol Anim Nutr (Berl). 99 (3): 405–417. doi:10.1111/jpn.12234. PMID 25099672. Retrieved 1 June 2016. Cholesterol is a major component of the cell membrane, and sarcolemma is the one that relies mainly on de novo synthesis of cholesterol. This is important under stressful conditions when muscle cells may lack the capacity to produce adequate amounts of the cholesterol that is essential to proper functioning of cell membranes. Many biochemical studies have shown that HMB may be a precursor of cholesterol synthesis (Bachhawat et al., 1955; Bloch et al., 1954; Coon et al., 1955; Adamson and Greenberg, 1955; Gey et al., 1957). According to pertinent literature, HMB carbon is incorporated into cholesterol. Therefore, increased intramuscular HMB concentrations may provide readily available substrate for the cholesterol synthesis that is needed to form and stabilize the sarcolemma. ... In theory, HMB use as a precursor to cholesterol could aid in stabilizing muscle cell membranes; however, this has not been confirmed by research studies.
^ Landi F, Calvani R, Tosato M, Martone AM, Ortolani E, Savera G, D'Angelo E, Sisto A, Marzetti E (May 2016). "Protein Intake and Muscle Health in Old Age: From Biological Plausibility to Clinical Evidence". Nutrients. 8 (5): 295. doi:10.3390/nu8050295. PMC 4882708. PMID 27187465. HMB exerts its effects through protective, anticatabolic mechanisms and directly influences protein synthesis. HMB has also been shown to stabilize the muscle cell membrane, to modulate protein degradation and to up-regulate protein synthesis [68]. ... More recently, Deutz and colleagues [13]—in a multicenter, randomized, placebo-controlled, double-blind trial—demonstrated that the early administration (within 72 h of hospitalization) of a nutrient-dense oral nutritional supplement containing high concentrations of protein and HMB was associated with decreased post-discharge mortality and improved nutritional status in malnourished older adults [13].
^ ^a ^b ^c ^d ^e ^f ^g ^h Argilés JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Mañas L (June 2016). "Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease". J. Am. Med. Dir. Assoc. 17 (9): 789–96. doi:10.1016/j.jamda.2016.04.019. PMID 27324808. Studies suggest dietary protein and leucine or its metabolite b-hydroxy b-methylbutyrate (HMB) can improve muscle function, in turn improving functional performance. ... These have identified the leucine metabolite β-hydroxy β-methylbutyrate (HMB) as a potent stimulator of protein synthesis as well as an inhibitor of protein breakdown in the extreme case of cachexia.^{65, 72, 76, 77, 78, 79, 80, 81, 82, 83, 84} A growing body of evidence suggests HMB may help slow, or even reverse, the muscle loss experienced in sarcopenia and improve measures of muscle strength.^{44, 65, 72, 76, 77, 78, 79, 80, 81, 82, 83, 84} However, dietary leucine does not provide a large amount of HMB: only a small portion, as little as 5%, of catabolized leucine is metabolized into HMB.⁸⁵ Thus, although dietary leucine itself can lead to a modest stimulation of protein synthesis by producing a small amount of HMB, direct ingestion of HMB more potently affects such signaling, resulting in demonstrable muscle mass accretion.^{71, 80} Indeed, a vast number of studies have found that supplementation of HMB to the diet may reverse some of the muscle loss seen in sarcopenia and in hypercatabolic disease.^{65, 72, 83, 86, 87} The overall treatment of muscle atrophy should include dietary supplementation with HMB, although the optimal dosage for each condition is still under investigation.⁶⁸ ...
Figure 4: Treatments for sarcopenia. It is currently recommended that patients at risk of or suffering from sarcopenia consume a diet high in protein, engage in resistance exercise, and take supplements of the leucine metabolite HMB. {{cite journal}}: External link in |quote= (help)
^ Rahman A, Wilund K, Fitschen PJ, Jeejeebhoy K, Agarwala R, Drover JW, Mourtzakis M (July 2014). "Elderly persons with ICU-acquired weakness: the potential role for β-hydroxy-β-methylbutyrate (HMB) supplementation?". JPEN J. Parenter. Enteral Nutr. 38 (5): 567–575. doi:10.1177/0148607113502545. PMID 24072740. More than 20 publications in humans have demonstrated benefit with HMB supplementation associated with increased lean body mass without fat gain, improved markers of muscle strength, and decreased onset of muscle soreness with training and reduced markers of muscle damage.^5,29

Seppi333 (Insert 2¢) 20:36, 29 April 2016 (UTC)[reply]

Thanks for posting those sources! I cannot believe how crappy that 2013 review is. Disturbing. Am going to open a discussion at WT:MED about it. Jytdog (talk) 18:16, 30 April 2016 (UTC)[reply]

@Jytdog: I've only read (mostly) through half of these, but it appears that the reviews that describe HMB's effects in general (i.e., not solely in the context of a pharmacotherapy for sarcopenia/muscle wasting) - ^[1]^[2] - draw the same or even stronger conclusions about its effects in humans compared to the ISSN review. I'll probably end up relying on the newer reviews for supporting statements about clinical effects, so using this source to independently support such statements won't be an issue.

Also, I'm considering taking this article to FA status since its primary clinical/therapeutic effect is unique and improving the article won't be too much work compared to other drug articles that I've worked on; there's only a handful of reviews and a few database refs from which to collate information on the compound, so finding all the relevant information to satisfy the comprehensiveness criterion won't be difficult (researching/revising amphetamine for FA took over a year; this would probably take ~1 month). With that in mind, if you have any feedback on the other sources or any other suggestions, I'd be interested to hear it. Seppi333 (Insert 2¢) 16:51, 20 May 2016 (UTC)[reply]

@Jytdog: Hey, sorry to bother you again with this request, but would you be willing to send me these 5 reviews?^[3]^[4]^[5]^[6]^[7] They're paywalled and I don't have access. I'd really appreciate it. Seppi333 (Insert 2¢) 22:28, 23 May 2016 (UTC)[reply]

I sent them all except PMID 23919746 which my library doesn't get. Jytdog (talk) 00:30, 24 May 2016 (UTC)[reply]

Thank you very much! I appreciate it. Hopefully I can get that last one from WP:RX. Seppi333 (Insert 2¢) 05:08, 24 May 2016 (UTC)[reply]

December 2016

Review of HMB's effects on skeletal muscle, pharmacodynamics, and pharmacokinetics from January 2016^[8]
Systematic review on supplements for cachexia from 2016^[9]

Seppi333 (Insert 2¢) 19:15, 5 December 2016 (UTC)[reply]

References

^ Cite error: The named reference Molecular Aspects of Medicine 2016 review was invoked but never defined (see the help page).
^ Cite error: The named reference PEDs in sports 2015 review was invoked but never defined (see the help page).
^ Cite error: The named reference HMB athletic performance-related effects 2011 review was invoked but never defined (see the help page).
^ Cite error: The named reference HMB for cancer cachexia 2013 review was invoked but never defined (see the help page).
^ Cite error: The named reference Effects of amino acid derivatives 2015 review was invoked but never defined (see the help page).
^ Cite error: The named reference Muscle atrophy-related signal transduction review was invoked but never defined (see the help page).
^ Cite error: The named reference Nutrition supplements for athletes 2014 review was invoked but never defined (see the help page).
^ Duan Y, Li F, Li Y, Tang Y, Kong X, Feng Z, Anthony TG, Watford M, Hou Y, Wu G, Yin Y (January 2016). "The role of leucine and its metabolites in protein and energy metabolism". Amino Acids. 48 (1): 41–51. doi:10.1007/s00726-015-2067-1. PMID 26255285. S2CID 254080284.
^ Mochamat, Cuhls H, Marinova M, Kaasa S, Stieber C, Conrad R, Radbruch L, Mücke M (July 2016). "A systematic review on the role of vitamins, minerals, proteins, and other supplements for the treatment of cachexia in cancer: a European Palliative Care Research Centre cachexia project". Journal of Cachexia, Sarcopenia and Muscle. 8 (1): 25–39. doi:10.1002/jcsm.12127. PMC 5326814. PMID 27897391.

Recent preclinical research

Covers HMB's effects on protein synthesis in brain cells, neurite outgrowth, and age-related dendritic remodeling in the brain of various nonhuman animals:
- Evidence that HMB is a (non-protein small molecule) neurotrophic factor in the brain of nonhuman animals (mice - in vitro/rats - in vivo)^[1]^[2]
- Increases protein synthesis in the mouse brain (in vitro) and pig brain (in vivo)^[1]^[3]

Seppi333 (Insert 2¢) 03:19, 28 May 2016 (UTC)[reply]

References

^ ^a ^b Salto R, Vílchez JD, Girón MD, Cabrera E, Campos N, Manzano M, Rueda R, López-Pedrosa JM (August 2015). "β-Hydroxy-β-Methylbutyrate (HMB) Promotes Neurite Outgrowth in Neuro2a Cells". PLOS ONE. 10 (8): e0135614. Bibcode:2015PLoSO..1035614S. doi:10.1371/journal.pone.0135614. PMC 4534402. PMID 26267903. In conclusion, we have shown for the first time that HMB promoted neurite outgrowth through PI3K/Akt and ERK1/2 signaling pathways in Neuro2a cells. Its effect in neuron differentiation is concomitant with higher levels of glucose transporters, the activation of mTOR by mTORC2 and consequently an increase in protein synthesis. Moreover, HMB is involved in promoting MEF2 activity and expression of members of this family of transcriptional factors. We believe that HMB may have great potential as [a neurotrophic] factor promoting neuron differentiation and plasticity. Our results indicated a novel effect of HMB on neurite outgrowth and call to further studies to reveal its positive influences on cognitive outcomes.
^ Kougias DG, Nolan SO, Koss WA, Kim T, Hankosky ER, Gulley JM, Juraska JM (April 2016). "Beta-hydroxy-beta-methylbutyrate ameliorates aging effects in the dendritic tree of pyramidal neurons in the medial prefrontal cortex of both male and female rats". Neurobiol. Aging. 40: 78–85. doi:10.1016/j.neurobiolaging.2016.01.004. PMID 26973106. S2CID 3953100.
^ Kao M, Columbus DA, Suryawan A, Steinhoff-Wagner J, Hernandez-Garcia A, Nguyen HV, Fiorotto ML, Davis TA (May 2016). "Enteral β-Hydroxy-β-Methylbutyrate Supplementation Increases Protein Synthesis in Skeletal Muscle of Neonatal Pigs". Am. J. Physiol. Endocrinol. Metab. 310 (11): E1072–84. doi:10.1152/ajpendo.00520.2015. PMC 4935142. PMID 27143558. The fractional rates of protein synthesis in the brain were greater in the piglets supplemented with HMB 40 and 80 or fed the HP diet compared to feeding the LP diet alone or the fasting condition (P < 0.05, Fig. 5, G).

mTOR signaling cascades

Leaving this here for personal reference.

Has a detailed mTOR signaling cascade diagram^[1]
Discusses and includes a diagram of signaling cascades involved in MPS/MPB^[2] hosted here temporarily

Seppi333 (Insert 2¢) 08:51, 1 June 2016 (UTC) Updated 00:42, 27 August 2016 (UTC)[reply]

References

^ Lipton JO, Sahin M (October 2014). "The neurology of mTOR". Neuron. 84 (2): 275–291. doi:10.1016/j.neuron.2014.09.034. PMC 4223653. PMID 25374355.
Figure 2: The mTOR Signaling Pathway
^ Anthony TG (July 2016). "Mechanisms of protein balance in skeletal muscle". Domest. Anim. Endocrinol. 56 Suppl (Suppl): S23–S32. doi:10.1016/j.domaniend.2016.02.012. PMC 4926040. PMID 27345321.

Metabolic pathway links

HMB-CoA HMDB entry
HMB-CoA KEGG entry
- 3-Hydroxyisovaleryl-CoA ⇔ 3-Methylcrotonyl-CoA + H2O – EC 4.2.1.17
- 3-Hydroxyisovaleryl-CoA ⇔ 3-Hydroxyisovalerate – "unclear reaction"
alpha-Ketoisocaproate + O2 ⇒ 3-Hydroxy-3-methylbutyrate + CO2 – EC 1.13.11.27; 4-hydroxyphenylpyruvate dioxygenase = KIC dioxygenase per ^[1]^[2]

Should be able to write a comprehensive biosynthesis/metabolism section using these 5 refs:

^[1] (covers α-KIC → HMB reaction)
^[2] (covers most of the metabolic pathway; has another diagram)
^[3] (covers HMB-CoA → HMB)
^[4] (covers most of the metabolic pathway; includes the same metabolic pathway graphic as the ISSN review)
ISSN review - PMID 23374455 (review with the article's current metabolic pathway graphic)

Seppi333 (Insert 2¢) 00:10, 7 June 2016 (UTC)[reply]

References

^ ^a ^b "Homo sapiens: 4-hydroxyphenylpyruvate dioxygenase reaction". MetaCyc. SRI International. 20 August 2012. Retrieved 6 June 2016.
^ ^a ^b Kohlmeier M (2015). "Leucine". Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. pp. 385–388. ISBN 9780123877840. Figure 8.57: Metabolism of L-leucine {{cite book}}: External link in |quote= (help)
^ Mock DM, Stratton SL, Horvath TD, Bogusiewicz A, Matthews NI, Henrich CL, Dawson AM, Spencer HJ, Owen SN, Boysen G, Moran JH (November 2011). "Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans". J. Nutr. 141 (11): 1925–1930. doi:10.3945/jn.111.146126. PMC 3192457. PMID 21918059. Reduced activity of MCC impairs catalysis of an essential step in the mitochondrial catabolism of the BCAA leucine. Metabolic impairment diverts methylcrotonyl CoA to 3-hydroxyisovaleryl CoA in a reaction catalyzed by enoyl-CoA hydratase (22, 23). 3-Hydroxyisovaleryl CoA accumulation can inhibit cellular respiration either directly or via effects on the ratios of acyl CoA:free CoA if further metabolism and detoxification of 3-hydroxyisovaleryl CoA does not occur (22). The transfer to carnitine by 4 carnitine acyl-CoA transferases distributed in subcellular compartments likely serves as an important reservoir for acyl moieties (39–41). 3-Hydroxyisovaleryl CoA is likely detoxified by carnitine acetyltransferase producing 3HIA-carnitine, which is transported across the inner mitochondrial membrane (and hence effectively out of the mitochondria) via carnitine-acylcarnitine translocase (39). 3HIA-carnitine is thought to be either directly deacylated by a hydrolase to 3HIA or to undergo a second CoA exchange to again form 3-hydroxyisovaleryl CoA followed by release of 3HIA and free CoA by a thioesterase.
^ Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (April 2011). "HMB supplementation: clinical and athletic performance-related effects and mechanisms of action". Amino Acids. 40 (4): 1015–1025. doi:10.1007/s00726-010-0678-0. PMID 20607321. S2CID 11120110. HMB is a metabolite of the amino acid leucine (Van Koverin and Nissen 1992), an essential amino acid. The first step in HMB metabolism is the reversible transamination of leucine to a-KIC that occurs mainly extrahepatically (Block and Buse 1990). Following this enzymatic reaction, a-KIC may follow one of two pathways. In the first, HMB is produced from a-KIC by the cytosolic enzyme KIC dioxygenase (Sabourin and Bieber 1983). The cytosolic dioxygenase has been characterized extensively and differs from the mitochondrial form in that the dioxygenase enzyme is a cytosolic enzyme, whereas the dehydrogenase enzyme is found exclusively in the mitochondrion (Sabourin and Bieber 1981, 1983). Importantly, this route of HMB formation is direct and completely dependent of liver KIC dioxygenase. Following this pathway, HMB in the cytosol is first converted to cytosolic b-hydroxy-b-methylglutaryl-CoA (HMG-CoA), which can then be directed for cholesterol synthesis (Rudney 1957) (Fig. 1). In fact, numerous biochemical studies have shown that HMB is a precursor of cholesterol (Zabin and Bloch 1951; Nissen et al. 2000).

In the second pathway, after transamination, a-KIC in liver generates isovaleryl-CoA through the enzymatic action of branched-chain ketoacid dehydrogenase (BCKD) and after several steps, there is production of HMG-CoA through the enzyme HMG-CoA synthase (Fig. 1). Under normal conditions the majority of KIC is converted into isovaleryl-CoA, in which approximately 5% of leucine is metabolized into HMB (Wilson et al. 2008; Van Koverin and Nissen 1992). However, Nissen and Abumrad (1997) provided evidence that the primary fate of HMB is probably conversion to HMG-CoA in the liver, for cholesterol biosynthesis.

FAC-related references

For Nergaal's review

WADA and NCAA refs

allowed by WADA and the NCAA^[1] Added
WADA banned substances list^[2] Added

Physical/Chemical properties and classification refs

Chemical taxonomy - http://www.hmdb.ca/metabolites/HMDB00754#taxonomy (already defined as <ref name="HMDB" />) Added
Parent compounds and the relationship between the acid/base^[3]^[4] Added

References

^ Rippe JM (2013). "Beta-Hydroxy beta-methylbutyrate". Lifestyle Medicine (2nd ed.). CRC Press. p. 724. ISBN 9781439845448. Retrieved 15 August 2016.
^ "List of Prohibited Substances and Methods: By Substance". World Anti-Doping Agency. 2016. Retrieved 15 August 2016.
^ "3-hydroxyisovaleric acid". Chemical Entities of Biological Interest. European Bioinformatics Institute. 23 October 2015. Retrieved 20 August 2016.
^ "3-hydroxyisovalerate". Chemical Entities of Biological Interest. European Bioinformatics Institute. 16 September 2014. Retrieved 20 August 2016.

For Jytdog's review

Primary clinical research involving Juven (3 g HMB + 14 g arginine + 14 g glutamine)

PMID 11975938 - 2002 trial of Juven for cancer cachexia
PMID 12192323 - 2002 trial examining the effect of Juven on collagen deposition
PMID 17215743 - 2007 trial examining the effects of Juven in critically ill trauma patients.
PMID 18293016 - 2008 Phase 3 clinical trial of Juven w/o exercise for cancer cachexia
PMID 26420181 - 2015 trial of Juven for postoperative recovery of quadriceps muscle strength after total knee arthroplasty
PMID 26306566 - 2016 trial with Juven examining the effect on vascular endothelial function in older adults after 6 months

Reviews covering clinical trials with Juven

PMID 23919746 - 2013 review that probably covers the phase 3 + other trials w/ Juven for cachexia (need to obtain this review)
PMID 25215468 - 2014 review of Juven for diabetic foot ulcers
PMID 24336486 / #cite_note-Nutrition_supplements_for_athletes_2014_review-14 - covers the effects of Juven on lean body mass+immune function in individuals w/ AIDS and lean body mass in individuals w/ cancer cachexia
PMID 24057808 / #cite_note-Systematic_review_December_2013-5 - relevant section quoted below

HMB mixed with other molecules in chronic diseases

Interesting results were observed during cancer, notably, patients with advanced (stage IV) cancer receiving a HMB/ ARG/GLN supplement gained 0.95 ± 0.66 kg of BM in 4 weeks and a change in body composition (FFM increase of 1.12 ± 0.68 kg). The FFM increase was maintained over the 24 weeks (May et al. 2002). Human immunodeficiency virus (HIV)-infected patients gained 3.0 ± 0.5 kg of BM after 8 weeks of HMB/ARG/GLN supplementation, mainly FFM (2.55 ± 0.75 kg). HMB/ARG/GLN supplementation also improved immune status, measured by increasing CD3 and CD8 cells and decreasing the HIV viral load. The HMB/ARG/GLN-supplemented group presented an increased BUN concentration due to higher nitrogen intake and trends towards lower triglyceride levels, higher protein and higher hemoglobin levels not due to treatment (Clark et al. 2000). Regarding haemoglobin, the magnitude of the response to HMB/ARG/GLN was more apparent in cancer patients compared to HIV patients and healthy volunteers. These results show that HMB/ARG/GLN can be safely used to treat AIDS- and cancer-related muscle wasting (Rathmacher et al. 2004). Berk et al. (2008) showed a strong trend towards higher FFM and BM in HMB/ARG/GLN-supplemented patients but they did not adequately test the ability of HMB/ARG/GLN to reverse or prevent cancer cachexia because most of patients did not complete the study. It was also demonstrated that both placebo and experimental amino acid mixtures significantly increased FFM, total body protein, arms and legs lean mass, and measures of physical function in rheumatoid arthritis patients but HMB/ARG/GLN supplementation was not superior to placebo in reversing rheumatoid cachexia (Marcora et al. 2005). No influence of HMB/ARG/GLN administration on the decrease in BM, body mass index (BMI), FFM and resting metabolic rate (RMR) after laparoscopic gastric bypass (LGB) was observed. Therefore, there was no potential preservation of FFM (Clements et al. 2011; Breitman et al. 2011). In addition, no effects on the early postoperative incretins after LGB, negative influence on insulin sensitivity, and degree of inflammatory markers after HMB/ARG/GLN administration were measured (Breitman et al. 2011).

— PMID 24057808 / #cite_note-Systematic_review_December_2013-5

For Nergaal+Axl's reviews (History section content)

^[1]

Metabolic Technologies, Inc. (MTI) is a small research and development company located in the Iowa State University Research Park in Ames, Iowa, with current sales just under $2 million annually. MTI was founded in 1990 with the vision of developing and marketing naturally derived products that enhance health, performance, and well-being. ...

Developed Products: The first commercial product developed was HMB® or β-hydroxy-β-methylbutyrate. This naturally occurring leucine metabolite has become a standard bearer in the sports nutrition market by having superior efficacy and safety data available. HMB is now protected under several patents. HMB is currently sold as a calcium salt, CaHMB.
The second commercial product MTI developed was Juven®. Juven® is a combination of arginine, glutamine, and HMB. Clinical studies showed that this product enhanced maintenance and restoration of muscle mass in both AIDS and cancer patients. In 2003, the rights to market Juven® were acquired by Abbott Nutrition. Abbott Nutrition currently markets Juven® for AIDS, cancer-cachexia, and wound healing.
Although not commercially developed yet, a third product, Re-Vigor®, was researched and designed by MTI. Re-Vigor® is a combination of arginine, lysine, and HMB, and is intended to slow down muscle wasting in the elderly. In 2008, the rights to this product were acquired by Abbott Nutrition. ...

As previously stated, MTI has been successful in transitioning HMB from an “exercise commodity” to that used by medical nutritional products (Juven® and Abound®-- Abbott Nutritional Laboratories).
— The University of Iowa Economic Development Grow Iowa Values Fund Proposal: Fiscal Year 2011

References

^ "The University of Iowa Economic Development Grow Iowa Values Fund Proposal: Fiscal Year 2011" (PDF). University of Iowa. pp. 13–16. Retrieved 1 September 2016.

Seppi333 (Insert 2¢) 00:55, 25 August 2016 (UTC)[reply]

Upcoming systematic review

"Beta-hydroxy-beta-methylbutyrate free acid improves resistance training-induced muscle mass and function: a systematic review" - anticipated completion (publication?) date: September 2016

Research question: What is the effect of HMB-FA on resistance training-induced muscle mass and function?

Primary outcomes:

Effects on skeletal muscle in sedentary, active and recreationally-trained subjects and HMB-supplemented compared with placebo.
Change in lean mass from baseline to final intervention.
Change in strength and biochemical parameters from baseline to final intervention.

Seppi333 (Insert 2¢) 11:45, 31 July 2016 (UTC)[reply]

Comment about safety

I'd like to start off by stating that I hope my commenting here does not turn away any potential GA reviewers since I believe these concerns can be addressed quickly, so much so that I'm tempted to go ahead and make them myself rather than post here, but I believe the prose will be more consistent if these changes are made by those who have written the majority of the article already.

In the opening there is a stand-alone sentence discussing HMB's safety in "young or old individuals", but to me that is a little unclear. The first source cited for that statement says "Chronic consumption of HMB is safe in both young and old populations", so I looked through it to see what they consider young. It appears they are referring to young adults as later in the paper they state that no research has been carried out on infants and very little research has been carried out on adolescents. Additionally no research appears to have been carried out on pregnant women.

With this in mind I would suggest further clarifying in the lead the lower bound of the age of individuals for which HMB supplementation appears safe. In addition the description of its safety in humans in the side effects section should be qualified so that it excludes human sub-populations that HMB hasn't been well studied in. Lastly the first sentence of that section implies that safety for animals in general has been established—"the safety profile of HMB in humans and animals"—this should be reworded/expanded to convey either which animals it has been found to be safe for, and/or to describe how animal models have been used to help establish the safety profile in humans. M. A. Bruhn (talk) 05:13, 3 August 2016 (UTC)[reply]

@M. A. Bruhn: I agree that this should be clarified.

I think specifying "young adults and older adults" should adequately address the ambiguity in the current phrasing. I actually wasn't aware that any clinical testing with the compound had been conducted on individuals who are younger than 18.
I imagine that based upon the current wording, one might infer that its safety status has been shown to be analogous to a US pregnancy category A drug; this isn't true, since as far as I know there hasn't been any RCT testing with HMB supplementation on pregnant women. While it's very likely true that the compound isn't teratogenic, we can't say this and it shouldn't be implied without an appropriate citation. I'll add a clause stating that no clinical testing has been conducted with supplemental HMB in pregnant women.
I'd intended to add data on toxicity testing in animal models earlier but later decided to forego it since I figured most people would be interested in clinical information in humans. If you think it's worth adding, I'd be happy to include this. ~~IIRC, animal testing has involved daily doses of 15 g in rats for a duration of 1+ months w/o adverse effects, but I'll need to double check that.~~ (edit: the doses given to rats were actually much higher based upon PMID 23374455 and PMID 25099672) I'll add the information about the animal, dose/dosage, and duration of testing to the article sometime today or tomorrow when I find the review that covers it. As for humans, clinical testing has involved 3 g daily doses for up to a year w/o adverse effects and 6 g daily doses for a couple of months w/o adverse effects in young adults. This would probably also be worth mentioning in the side effects section, so I'll include this as well when I add the information on animal testing.
On a related note, the only thing I could probably put into an OD section is the LD₅₀ for rodent species; since LD₅₀ in non-human animals seldom accurately reflects the LD₅₀ for humans, I decided to forego the overdose section altogether.

I'll start working on making these changes now. Please let me know if you have any other suggestions for improvement; I'd be happy to act on them. Also, feel free to edit the article yourself and make any changes that you know are supported by references. I don't bite.

Seppi333 (Insert 2¢) 06:02, 3 August 2016 (UTC)[reply]

I'm going to add the information on high-dose animal testing a little later since I need to log off for now. I think I've addressed most of the issues you've raised here, so let me know what you think when you get a chance. Seppi333 (Insert 2¢) 07:23, 3 August 2016 (UTC)[reply]

Those changes have mostly addressed everything for me. The only concern I have is with the ambiguity of "animals". From the context it can be reasonably inferred by the average reader to refer to animals commonly used in research to predict effects in humans, but not all readers might make inference. Although it's unlikely that someone's going to believe it's referring to coral reefs and bumble bees, the statement as it is presently worded is grammatically stating that HMB is safe for animals in general. I think it just needs to be slightly reworded so that instead stating "The safety profile of HMB in ... animals has been well-established...” it instead more explicitly conveys that the animals which HMB appears safe in are animals used to gauge safety for humans. Maybe something along the lines of "The safety profile of HMB in adult humans has been well-established by medical reviews looking at a combination of randomized controlled trials in humans as well as extensive animal testing." I haven't read the medical reviews so I don't know if this is a good characterization or not.
I agree that data on animal models is probably irrelevant to add. I said that information on safety of specific animals could be added just on the off chance that there was information that was useful in it of itself, for instance if there had been any research on using HMB supplementation to bulk up livestock. But if that's not the case then there wouldn't seem to be a reason to make any specific mention of animal testing except in cases where it introduces something that human testing hasn't covered, such as with the pregnant pigs. I think making an OD section just for the LD50 might be giving it undue weight. I notice that the chem infoboxes have an LD50 parameter but the drug infoboxes do not, so perhaps that is an indication that LD50's for drugs shouldn't be presented in the infoboxes either. I'm neither for or against addition of such information, and think you should just do what you prefer.

I'll let you know if I see anything else or feel free to do it myself. Thanks and good luck with your editing.M. A. Bruhn (talk) 08:35, 3 August 2016 (UTC)[reply]

I used your proposed wording, which was accurate, and indicated that most of the animal testing has involved lab rats, pigs, chickens, and turkeys. Edit: the review on HMB supplementation in animals (PMID 25099672) states that "the utility of HMB supplementation in animals has been shown in numerous studies, which have demonstrated enhanced body weight gain and carcass yield in slaughter animals", but I'm going to look for other sources that cover its use in livestock for this purpose before covering it in the article since I don't know how common/notable this practice is. Seppi333 (Insert 2¢) 09:24, 3 August 2016 (UTC); edited at 14:17, 3 August 2016 (UTC)[reply]

@M. A. Bruhn: How would you feel about the addition of this statement to the paragraph on pregnancy?

As of 2016^[update], Metabolic Technologies Inc., the company that grants licenses to include HMB in dietary supplements, advises pregnant and lactating women not to take HMB due to a lack of safety studies conducted with this population.^[1]

I'm hesitant to add this, although I think it's notable since this is the company that grants licenses to allow the inclusion of HMB in dietary supplements. The reference is a primary source for the statement, but the statement itself is advisement as opposed to a medical claim. Seppi333 (Insert 2¢) 02:45, 23 August 2016 (UTC)[reply]

Edit: I decided to add this material to a newly created "Contraindications" section, since IMO this content is most appropriate there. Seppi333 (Insert 2¢) 04:19, 23 August 2016 (UTC)[reply]

I'm not sure how I feel about this source's inclusion. Companies will produce statements instructing consumers not to use their products in certain ways simply because 1) they want to avoid liability and 2) they know their consumers will ignore them anyways (like with consumers using Q-tips to clean their ears). When you first posted I spent some time trying to find a more MEDRS compliant source to use instead, I found several RS sources, but no MEDRS though. If it is qualified as "Company X says Y" then it isn't really an issue of accuracy (since they do indeed state this) so much as weight. I'm not sure if it is undue weight or not. If this were a drug then it would be easy to find alternative sources, but since it is a supplement our options are limited. I suppose I am leaning more towards its inclusion, but would prefer it if a better source could replace it. M. A. Bruhn (talk) 06:42, 29 August 2016 (UTC)[reply]

fwiw I think that Seppi is trying like crazy to cover all the sections in MEDMOS and cover the things we usually cover; for medicines we usually give the formal pregnancy category. A drug label will generally give the information as to whether the drug has been tested in pregnant women, or not and the label will give the negative information. In this case neither the label for Juven nor the label for the medical food Ensure discusses pregnancy. Neither of the current FDA draft guidances on medical food (not this and not this discuss pregnancy categories, and I am ~guessing~ that this is because medical food is well, food. Not something strange like a drug.

Because of all that, Seppi, I think there is no need to talk about the pregnancy thing; not until this is marketed as a drug (which I am guessing it never will be)

That said, I still think including the statement by the company, with attribution as suggested by M A Bruhn above, is a very good move. Jytdog (talk) 07:00, 29 August 2016 (UTC)[reply]

Yeah... I've been looking for medical sources that make a statement about HMB use during pregnancy or that cover a rather obvious drug interaction between HMB and rapamycin and/or mTOR inhibitors in general, but haven't really found suitable sources for either. In the case of the pregnancy statement in the article, I figure I can get away with that source since it doesn't really make any medical claims about HMB. It's basically just the company's advice, so I agree that it is more of a WP:DUE issue than a WP:RS/MEDRS issue.

As for the HMB/rapamycin interaction, their opposing effects on MTORC1 activation and protein synthesis is mentioned only in this primary source, which I can't use to cite a drug interaction. Seppi333 (Insert 2¢) 21:09, 29 August 2016 (UTC)[reply]

Reflist

References

^ "Who should not take HMB?". Metabolic Technologies, Inc. Retrieved 23 August 2016. Pregnant or lactating women are advised against taking HMB because safety studies have not yet been conducted for these populations.

Page name

The page name doesn't seem to be the most obvious choice to be. Thinking about WP:NAMINGCRITERIA I might suggest as alternatives (in rough order of preference):

HMB, on the grounds of Conciseness and Recognizability. It might then require the existing HMB to be moved to HMB (disambiguation)
beta-hydroxyisovaleric acid, on the grounds of Naturalness (MESH heading term)
3-hydroxy-3-methylbutanoic acid, on the grounds of Precision (IUPAC name)

Thoughts? If there is a decision for no change, then I think the last 2 terms should also be redirects here. Klbrain (talk) 18:38, 3 August 2016 (UTC)[reply]

I'll respond to these in reverse order:

3-hydroxy-3-methylbutanoic acid is neither more nor less precise than the current article name, both names only specify one molecule.
The main issue with beta-hydroxyisovaleric acid is that the common acronym, HMB, doesn't work for it. Additionally it seems that it isn't the preferred term in current literature.
There are specific naming guidelines based off of the topic. WP:NCMED gives the naming guidelines for medical articles and states "The article title should be the scientific or recognised medical name that is most commonly used in recent, high-quality, English-language medical sources". Furthermore it states that drugs should be titled based off their International Nonproprietary Name, although I'm fairly certain HMB does not have an INN, and the line between drug and supplement is blurry. The chemistry naming guidelines at WP:NCCHEM generally recommend this quoted section from the general naming conventions: "Generally, article naming should give priority to what the majority of English speakers would most easily recognize, with a reasonable minimum of ambiguity, while at the same time making linking to those articles easy and second nature". I think it might be best to look at other dietary supplements for guidance, and looking at other dietary supplement articles it appears using an acronym in place of the chemical name is not normally done, although perhaps a broader discussion should be had on the topic in a more general forum. M. A. Bruhn (talk) 20:46, 3 August 2016 (UTC)[reply]

The vast majority of literature that has been published on this compound from the past 20 years has used the terms "β-hydroxy β-methylbutyrate" [213 hits] or "β-hydroxy β-methylbutyric acid" [10 hits] (some sources also hyphenate "hydroxy-β"), depending on whether the study involved the conjugate base or acid. Prior to that, the 3- and β- "hydroxyisovalerate/hydroxyisovaleric acid" terms were more common. For comparison, the MESH name "beta-hydroxyisovaleric acid" gets only 8 results out of the 247 papers that are found from an unfiltered search using any of the MESH-indexed synonyms. The IUPAC name is seldom used in published literature.

Most commercial products contain the calcium salt of this compound and refer to it as "calcium hydroxymethylbutyrate", "calcium β-hydroxy β-methylbutyrate", or "calcium β-hydroxy β-methylbutyrate monohydrate" (again, some also hyphenate "hydroxy-β"), so I imagine that most of the incoming traffic to this article uses one of those terms. I'm more inclined to use the conjugate base as the page name since it's more prevalent in published literature, but it seems more common to use the acid than the base as the page title when there aren't separate articles for the conjugate acid/base forms of a compound (in this case, the acid/base forms of HMB should be covered in the same article). Consequently, I think the current page name is acceptable even though it's not the most common name. I'm open to renaming the article though. Seppi333 (Insert 2¢) 22:01, 3 August 2016 (UTC)[reply]

New sources

@Jytdog: Thanks for doing a literature search and posting these sources here; I really appreciate it! I'll read through and use them to write new content when I get a chance later today or tomorrow. Seppi333 (Insert 2¢) 21:26, 9 September 2016 (UTC)[reply]

I've been busier than I expected off-wiki over the past few days. I should have time to follow-up on this tomorrow night. Seppi333 (Insert 2¢) 22:48, 12 September 2016 (UTC)[reply]

@Jytdog: My bad for not doing this yet; I'm going to stop trying to give myself further deadlines that I can't meet due to how busy I've been this past week. I will, however, use the sources that you linked below to add content before I look for sources to cite for adding a statement on the calcium content of HMB-Ca. Seppi333 (Insert 2¢) 23:40, 16 September 2016 (UTC)[reply]

That's OK - the fitzpatrick book is already used and there is not much else here that is useful. I was mostly recording my work actually trying to track down sales.. Jytdog (talk) 23:43, 16 September 2016 (UTC)[reply]

@Jytdog: Oh. Well, I'll still look through them anyway - might have something worth adding. Also, one of the refs that you linked to at FAC mentioned something you might be interested in (see the bold+underlined text below). As of when this ref was published, all of MTI's products contained HMB, as stated in the quote. As of now, they also sell or license one product which contains no HMB: an adenosine triphosphate (ATP) supplement which they call "betaATP".

Seppi333 (Insert 2¢) 00:44, 17 September 2016 (UTC)[reply]

FWIW, based upon the prices of currently available HMB-Ca and HMB-FA supplements and the relative efficacy in primary studies between HMB-FA and HMB-Ca, I really doubt MTI is making close to $10,000,000 annually on HMB-FA alone. Seppi333 (Insert 2¢) 00:51, 17 September 2016 (UTC)[reply]

Metabolic Technologies 2011 sales + 5-year sales projections

Commercial Potential for the HMB Delivery System for Iowa: Metabolic Technologies, Inc. (MTI) is a small research and development company located in the Iowa State University Research Park in Ames, Iowa, with current sales just under $2 million annually. MTI was founded in 1990 with the vision of developing and marketing naturally derived products that enhance health, performance, and well-being. Central to this vision, MTI ensures that products are not marketed before quality manufacturing is guaranteed, safety is proven, and effectiveness is scientifically verified. MTI’s vision results in highly effective products that have definably superior safety margins. In addition, the vitality of the company is assured by focusing on strong patent protection for the products developed.
Developed Products: The first commercial product developed was HMB® or β-hydroxy-β- methylbutyrate. This naturally occurring leucine metabolite has become a standard bearer in the sports nutrition market by having superior efficacy and safety data available. HMB is now protected under several patents. HMB is currently sold as a calcium salt, CaHMB.
The second commercial product MTI developed was Juven®. Juven® is a combination of arginine, glutamine, and HMB. Clinical studies showed that this product enhanced maintenance and restoration of muscle mass in both AIDS and cancer patients. In 2003, the rights to market Juven® were acquired by Abbott Nutrition. Abbott Nutrition currently markets Juven® for AIDS, cancer-cachexia, and wound healing.
Although not commercially developed yet, a third product, Re-Vigor®, was researched and designed by MTI. Re-Vigor® is a combination of arginine, lysine, and HMB, and is intended to slow down muscle wasting in the elderly. In 2008, the rights to this product were acquired by Abbott Nutrition.
Current Product: We anticipate that the HMB free acid gel delivery system will replace the need for three daily doses of CaHMB, and thus will be a more efficient form of delivery and use in the exercise market. In addition, we anticipate that the ease of delivery of the free acid gel form will expand the current market potential for use of HMB as a nutritional supplement aimed at ameliorating tissue inflammation a condition that is prevalent in many diseases such as obesity, type 2 diabetes, rheumatoid arthritis, cardiovascular diseases and others. Data generated from this proposal will be used to apply for NIH Phase I and Phase II SBIR grants with potential funding of $1,150,000. In addition, the results from the proposed studies will be used to support a provisional U.S. patent that was filed in December of 2009.

Based on our current sales of CaHMB, we anticipate that the sales of HMB free acid gel in the exercise market will reach $10,000,000 annually by the 5th year. Our projected sales in the larger nutritional supplement market could easily exceed this amount and could reach 20-30 million USD by the 5th year. As previously stated, MTI has been successful in transitioning HMB from an “exercise commodity” to that used by medical nutritional products (Juven® and Abound®-- Abbott Nutritional Laboratories). We anticipate adding 10-20 new full-time positions within the next 3-5 years. These positions would be in the areas of research and development, quality control, sales, marketing, advertising and accounting.
— The University of Iowa Economic Development Grow Iowa Values Fund Proposal: Fiscal Year 2011

sources for extent of use of HMB

am looking for sources for this, will record what I find here. others are free to add of course...

This is really hard as MTI is a private company so have no obligation (and don't) report sales.

Shelly Meltzer, Cecily Fuller (2007). The Complete Book of Sports Nutrition: A Practical Guide to Eating for Sport. New Holland Publishers. p. 94. ISBN 9781845370817. -- says that 10,300 athletes at the 2000 Summer Olympics were tested for doping, and of them, 2758 were surveyed about their use of supplements. 24 of them said they used HMB. (for comparison, 1996 used some kind of vitamin)

Nuckols, Greg (July 20, 2016). "The HMB Controversy: Better than Steroids?". Strengtheory. (not a great ref, but guy who runs it seems to be not insignificant in world of lifers, see here). Has a blog entry focused on primary sources PMID 24599749 published in 2014 and the followup PMID 24714541 published this July and their remarkable results, and writes: "A supplement that’s been around for a long time, but which isn’t all that popular, works better than steroids?". "which isn't all that popular". Not much but something.

Eichner, E. Randy; King, Douglas; Myhal, Mark; Prentice, Bill; Ziegenfuss, Tim N. (1999). "Roundtable: "Muscle Builder" Supplements" (PDF). RT#37. 10 (3). again really slim. From 1999. One of roundtable participants says: "HMB sales declined rapidly after it was introduced because it had no perceived effect on muscle mass and was expensive." Same person also said: "Likewise, HMB has not lived up to its marketing hype as an anabolic agent" Another, " Among athletes who want to gain muscle mass, protein and creatine supplements are popular, especially in football, wrestling, and track and field. HMB and the banned substances DHEA and the “andros” are used by few or none"

This is all I found in a google search 10 pages out. Will check my library... Jytdog (talk) 21:10, 9 September 2016 (UTC)[reply]

sources on business background and marketing

Fitzgerald M (2014). Diet Cults: The Surprising Fallacy at the Core of Nutrition Fads and a Guide to Healthy Eating for the Rest of US. Pegasus Books. p. 147. ISBN 978-1-60598-595-4. -- has a passage describing the origin of Metabolic Technologies. Also discusses the science a bit - says early research was hyped, and notes the 2009 review that found it had some benefit for people just starting a training regimen but not for people who have been at it longterm.

Conis, Elena (29 May 2011). "Muscle drink with HMB targets the middle-aged". Los Angeles Times. -- "hook" was launch of Ensure Muscle Health; discusses that HMB is marketed to older/middle aged folks who want to start getting into shape, because that is who benefits the most (citing the 2009 review again)

Kane, Ed (September 2014). "Nutritional Supplements in Horses" (PDF). Insider. Animal Health International, Inc. pp. 11–15. - a trade rag, notes that HMB is marketed for horses but there is "little to no data to support its use in horses".

Same search as above. Jytdog (talk) 21:10, 9 September 2016 (UTC)[reply]

Mg of ionic calcium per gram of pure HMB from HMB-Ca

Need to find a WP:RS-quality source for this, since I think it's worth covering. Probably should be mentioned in the article since the {{mineral supplements}} navbox links here and most HMB-Ca brands don't appear to list this information on the supplement bottles. Seppi333 (Insert 2¢) 23:40, 16 September 2016 (UTC)[reply]

Placement of biosynthesis section

Biosynthesis is currently a subsection pharmacology/pharmacokinetics. Pharmacokinetics is what the body does to the drug, not how the body synthesizes it. Also some bugs and I assume many other "critters" synthesize HMB. Hence logically biosynthesis should not be a subsection of pharmacokinetics, but rather the chemistry (or possibly a new biochemistry) section. The reason I ask is that MC-CoA is used in the biosynthesis of a tetrasaccharide produced by Bacillus anthracis (anthrax bacteria) and HMB itself has been used in the laboratory synthesis of this tetrasaccharide (see PMID 15152001, 20614885). This new material would not be appropriate to add to the pharmacokinetics section but would be appropriate in a new biochemistry section. Thoughts? Boghog (talk) 09:13, 25 September 2016 (UTC)[reply]

I'm okay with moving it. I recognized that it wasn't really relevant to the PK section when I created it under that heading, but I put it there anyway simply because the HMB metabolism diagram also illustrates HMB biosynthesis. Seppi333 (Insert 2¢) 10:33, 25 September 2016 (UTC)[reply]

Expansion of chemistry section

Moved to Wikipedia:Featured article candidates/Beta-Hydroxy beta-methylbutyric acid/archive1

With thanks to Sizeofint for supplying database searches, I have expanded the synthesis section. There are several more syntheses that could be added, but most of these are obscure reactions or reactions where HMB is a side product. Hence I question the notability of these. Also there were some early syntheses reported (and associated physical data of the synthesized HMB) based on an aldol condensation without dehydration between acetone and ethyl acetate. However I think this would be highly unlikely since the dehydration is the driving force for the reaction. As far as physical data, there is not much more that could (or should) be added. By far, the most notable aspect of HMB is that is a naturally produced metabolite and a food additive . Much less has been published about its chemistry. Hence per WP:DUE, it is appropriate that the chemistry section of this article is significantly shorter than some of the other sections. Boghog (talk) 09:35, 25 September 2016 (UTC)[reply]

@Boghog: you should probably post this in Nergaal's review section to discuss with him what should or could be added about to HMB's chemistry. He's the only reviewer who has commented on the chemistry section thus far. Seppi333 (Insert 2¢) 17:52, 26 September 2016 (UTC)[reply]

History → Synthesis section split

@Boghog: I split part of the material that you added to the history section to the synthesis section and re-added a slightly duplicate statement about its very first reported synthesis to the history section in this edit. Is that okay with you? Seppi333 (Insert 2¢) 16:52, 9 November 2016 (UTC)[reply]

Yes. I was thinking of doing something similar. Thanks for taking care of that. Boghog (talk) 17:32, 9 November 2016 (UTC)[reply]

In the body

Moved to Wikipedia:Featured article candidates/Beta-Hydroxy beta-methylbutyric acid/archive2 § Comments by Doc James

Follow-up from FAC

Moved from Wikipedia:Featured article candidates/Beta-Hydroxy beta-methylbutyric acid/archive2 § Arbitrary section break2

The content in this tab has been moved again; it's now located at Wikipedia:Featured article candidates/Beta-Hydroxy beta-methylbutyric acid/archive3#Comments by Doc James.
Please continue this discussion there.

The review you are using comes to three sentences of conclusions

"HMB contributed to preservation of muscle mass in older adults." which says it help keep mm mass, does not comment on those with sarcopenea.

"HMB supplementation may be useful in the prevention of muscle atrophy induced by bed rest or other factors." A decrease of uncertainty

"Further studies are needed to determine the precise effects of HMB on muscle strength and physical function in older adults." Means it is unclear if HMB affects str or function. Doc James (talk · contribs · email) 03:04, 17 December 2016 (UTC)[reply]

IMO before we should be uneqivacally recommending this stuff in WP's voice I would like to see (1) government sources supporting benefit (2) specific reviews supporting benefit (which we have some of) and (3) general reviews supporting benefit. I do not see us as having either 1 or 3. Doc James (talk · contribs · email) 03:09, 17 December 2016 (UTC)[reply]

2017 general review on sarcopinea says "A recent meta-analysis revealed some benefit of using a combined approach of dietary supplements and exercise, but the findings were inconsistent among various populations." PMID:27886695

Based on this 2015 review [1] "The main message is that enhanced benefits of exercise training, when combined with dietary supplementation, have been shown in some trials – indicating potential for future interventions, but that existing evidence is inconsistent." Doc James (talk · contribs · email) 03:30, 17 December 2016 (UTC)[reply]

@Doc James: I've used more or less the exact wording from the meta-analysis' actual conclusion, as opposed to the abstract, in the lead in this edit. The body of the article already stated the part of the sentence that I added to the lead. This link will take you to the full text of the meta-analysis if you want to read the full conclusion.

"Further studies are needed to determine the precise effects of HMB on muscle strength and physical function in older adults." Means it is unclear if HMB affects str or function. Yes, I agree that what you stated is what that sentence means. The article didn't contradict this assertion before and it still doesn't now. The body of the article repeated that same assertion using different language at the time that you wrote this comment. I added the statement to the lead since you mentioned it.
IMO before we should be uneqivacally recommending this stuff in WP's voice I would like to see (1) government sources supporting benefit (2) specific reviews supporting benefit (which we have some of) and (3) general reviews supporting benefit. - we are not and have not been recommending anything. The article makes statements about efficacy in older adults based upon a meta-analysis. In the body of the article only, it states that the authors of two reviews have recommended it. If there are reviews that do not recommend it, we can state that too.
Re (1): why can't we just state that no governmental health agencies have endorsed the use of HMB?

Re (3): what is a "general review"?
Based on this 2015 review [2] "The main message is that enhanced benefits of exercise training, when combined with dietary supplementation, have been shown in some trials – indicating potential for future interventions, but that existing evidence is inconsistent." - this is consistent with what the meta-analysis states about the combination of exercise+HMB: "While effects on muscle mass were consistent, outcomes for muscle strength and physical performance varied in different reports. Perhaps resistance exercise in combination with HMB treatment is a potent stimulus for muscle improvement. Further studies are needed to investigate the combination of HMB and exercise for improving muscle strength and physical performance." Both reviews appear to support the assertion that "the effects of HMB combined with exercise on muscle strength and performance require further research in older adults", so would you like to see this statement added?
2017 general review on sarcopinea says "A recent meta-analysis revealed some benefit of using a combined approach of dietary supplements and exercise, but the findings were inconsistent among various populations." PMID:27886695 - this review cites this review which did not conduct a meta-analysis (quote from methodology: The studies were not graded for quality; no attempt at a meta-analysis was made.) but cited this meta-analysis when stating "A meta-analysis of findings from randomized controlled trials has shown that protein supplementation during an exercise training program increases gains in muscle mass and strength, in younger (<50 years) and older (≥50 years) adults16 – much less is known about the combined effects of exercise training and supplementation with other dietary components that have been linked to sarcopenia." That meta-analysis doesn't mention HMB anywhere. Seppi333 (Insert 2¢) 08:37, 17 December 2016 (UTC)[reply]

Just reade a few changes (diff) that i think reflect the refs and put the body and lead in harmony... calibration is very tricky here. are there outstanding issues? Jytdog (talk) 08:42, 18 December 2016 (UTC)[reply]

I'm ok with the changes you made relative to medical foods. Since the efficacy for sarcopenia has been such a major point of conflict, I think we should use language which is as close to the source as possible without creating a copyvio from paraphrasing too closely. Seppi333 (Insert 2¢) 19:36, 19 December 2016 (UTC)[reply]

@Doc James: Can you respond to my questions from above? Also, please let me know if you think Jytdog's and my changes to the first three sentences in the lead resolve the issues you had with the efficacy and the medical food statements. Seppi333 (Insert 2¢) 19:39, 19 December 2016 (UTC)[reply]

Jytdog's use of "may" is much better than "can" based on my reading of the evidence. We have the concern that this stuff has not actually been studied in people with sarcopenia, we have the issue of the small number of peoples in the trials, and than we have the issue of other sources using more tentative language. Doc James (talk · contribs · email) 19:42, 19 December 2016 (UTC)[reply]

Have moved the marketing claims to the 4th paragraph.[3] Likely just needs one reference rather than 4 as all supported by PR Newswire Doc James (talk · contribs · email) 19:47, 19 December 2016 (UTC)[reply]

I've removed the link to sarcopenia in the lead sentence since you feel that this is an issue. Seppi333 (Insert 2¢) 19:48, 19 December 2016 (UTC)[reply]

That was not my issue and this does not address my concerns[4] Doc James (talk · contribs · email) 19:48, 19 December 2016 (UTC)[reply]

You said We have the concern that this stuff has not actually been studied in people with sarcopenia. I've removed sarcopenia from the lead and simply indicated it's people with age-related muscle loss, which is supported by the title of the meta-analysis and the demographics included in the meta-analysis. The modified sentence is almost identical to the sentence in the conclusion of the meta-analysis, with superficial wording differences. Why is that sentence still an issue? It's clearly not an overstatement of efficacy per the meta-anaylsis. Edit: the article says "HMB can inhibit the loss of lean body mass in individuals experiencing age-related muscle loss"; the meta-analysis says "Overall, this meta-analysis indicates that HMB can prevent lean body mass loss in older adults." What the meta-analysis says is stronger than what the article says because prevent means "completely avoid", whereas inhibit just means "reduce". I'm not okay with downplaying the efficacy anymore than that.Seppi333 (Insert 2¢) 19:51, 19 December 2016 (UTC)[reply]

Entire conclusion from the meta-analysis

From [5]:

5. Conclusion
Overall, this meta-analysis indicates that HMB can prevent lean body mass loss in older adults. But the effects of HMB on muscle strength and physical function appears to vary in different populations. Additional well-designed clinical studies are necessary to confirm the effectiveness of HMB in the prevention of loss of muscle strength and physical function.

@Doc James: What is your concern with that sentence, specifically, if the population samples included in the RCTs from that meta-analysis (link here) wasn't the issue? Seppi333 (Insert 2¢) 00:00, 20 December 2016 (UTC)[reply]

Seppi, above you wrote: " I've removed sarcopenia from the lead and simply indicated it's people with age-related muscle loss". That is not any change in meaning, right? Jytdog (talk) 01:54, 20 December 2016 (UTC)[reply]

@Jytdog: sarcopenia and age-related muscle loss aren't entirely synonymous. Sarcopenia is a medical diagnosis that involves the loss of lean body mass, whereas the loss of muscle mass associated with age is simply a phenomenon that typically starts to occur in the late 30s or mid-40s and accelerates with each additional decade. Before that point, the human body is on average in an anabolic state, and muscle growth tends to occur annually even without exercise. After that age range, the body is on average in a catabolic state, and muscle mass tends to decline on an annual basis. The meta-analysis included studies in which the samples contained primarily healthy older adults who did not have a diagnosis of sarcopenia. Some of the participants may have been sarcopenic, but to my knowledge none were diagnosed as such.

The fact that the participants in most of the studies were not diagnosed with sarcopenia is one of the issues that Doc James correctly pointed out earlier. We shouldn't say that the meta-analysis applies to adults diagnosed with sarcopenia. Its conclusion really only applies to older adults in general, almost all of whom experience annual losses in muscle mass if they don't perform resistance exercise on a regular basis. Seppi333 (Insert 2¢) 02:24, 20 December 2016 (UTC)[reply]

New reviews

Checked for updates on November 9th, 2017 (my birthday, yay). Seppi333 (Insert 2¢) 05:33, 9 November 2017 (UTC)[reply]

Happy Birthday :-) Doc James (talk · contribs · email) 05:37, 9 November 2017 (UTC)[reply]

Thanks!

Seppi333 (Insert 2¢) 06:12, 9 November 2017 (UTC)[reply]

1st

Added (partially) - more potential material to go through and add if deemed encyclopedic; see collapse tab below

@Jytdog, Boghog, and Doc James: I just did a literature search and found one new review: PMID 28493406;^[1] it was published online on May 10, 2017. Also, I contacted the corresponding author of this prospective systematic review a few weeks ago; he told me that it has been submitted to an academic journal and is currently being peer-reviewed, so I suspect that it will be published within the next 1–3 months. Once it's published, I intend to add a summary of its findings on the effects/efficacy of HMB in healthy individuals.

As for this^[1] review, I intend to use it to cite existing statements and possibly add new material which is relevant to clinical uses (e.g., HMB supplementation in elderly/sarcopenic individuals). These are the sections from the review that are relevant to its clinical uses:

Excerpts of the sections on Elderly populations, Toxicity + adverse effects, and Conclusions

Elderly and effects of HMB supplementation

Sarcopenia, which is present in approximately 5 to 10% of persons over 65 years of age is associated with weakness, falls, and a decreased ability to respond to illness or injury.[60] Muscle wasting may be exacerbated during a period of disuse during a prolonged bed rest and by decreased food intake, particularly during an illness.

A hallmark of sarcopenia in elderly subjects is a decreased ability to increase muscle protein synthesis in response to anabolic signals such as food intake and resistance exercise. In other words, this condition suppresses the stimulatory effect of food and other signals on mRNA translation, the rate-controlling step for protein synthesis, which is primarily regulated by the mTOR signalling pathway. Such anabolic resistance of muscle to nutrients is probably due to oxidative stress and low-grade inflammation.

There is growing evidence that the severe decreases in the skeletal muscle mass and function that occur with ageing may be mitigated by HMB supplementation (Table 3). Based on the meta-analysis of seven randomized controlled trials, HMB supplementation can prevent the loss of lean body mass in older adults without causing a significant change in fat mass.[72] The rationale for HMB supplementation in ageing subjects is strongly supported by recent findings of a negative correlation between the HMB levels in blood plasma with age and the lower levels of KIC dioxygenase in the livers of old rats than in young rats.[73]
— ^[1]

Toxicity and adverse effects

Several studies have demonstrated that supplemental HMB is well tolerated and has no toxic effects.[11, 100, 117] However, although HMB is made naturally by the body, it is possible that the positive effects of HMB on the protein balance in muscle may exert some adverse effects in other tissues. Stimulation of protein synthesis and suppression of proteolysis by HMB decreases the release of various amino acids from muscles to the blood and may impair their availability in visceral tissues. Glutamine is of particular interest on the basis that it acts as an essential substrate for enterocytes and immune cells and its deficiency decreases protein synthesis in skeletal muscle.[118, 119] The plasma glutamine concentration is already low in many patients with critical illness, and a decreased glutamine level has been reported after HMB treatment.[22] Therefore, studies are needed to examine whether the positive effects of HMB on muscle mass in cachexia are associated with glutamine depletion and adverse effects in other tissues.

Conclusions

The reports summarized here indicate that HMB provides a number of benefits to subjects involved in strength-power and endurance sports. The effects on muscle mass and strength, particularly during resistance training, are likely related to the suppression of proteolysis and a positive effect on protein synthesis. Its benefits in aerobic performance are probably more associated with improved mitochondrial biogenesis and fat oxidation. Favourable effects on the recovery from exercise-induced damage may be related to the role of HMB as a precursor of cholesterol, which modulates membrane fluidity and affects ion channels, and membrane excitability.

Studies have demonstrated that HMB can prevent the development of sarcopenia in elderly subjects and that the optimal action of HMB on muscle growth and strength occurs when it is combined with exercise. Unfortunately, exercise is performed only by a small percentage of elderly subjects. Several studies suggest that HMB supplementation is ineffective in healthy sedentary subjects.

Studies performed under in vitro conditions and animal studies suggest that HMB may be effective as a treatment for muscle wasting in various forms of cachexia. However, clinical reports are rare, and most of them examined the therapeutic potential of combinations of various agents. It was therefore not possible to determine, which of the supplements was effective. Further studies examining the effects of HMB administered alone are needed to reach a conclusion regarding the specific effectiveness of HMB in attenuating muscle wasting in a range of catabolic conditions. Although most of the endogenous HMB is produced in the liver and impaired HMB production may be assumed to occur in liver disease, there are no reports regarding the metabolism of HMB and the effects of its supplementation in subjects with liver disease.
— ^[1]

Also, check for new pharmacology content to add from these sections of the review:

Effects on protein metabolism in skeletal muscle
Effects on leucine metabolism
Effects on cholesterol metabolism
Exercise performance and effects of HMB supplementation

For myself: unrelated excerpt on an animal study
Apart from the benefits to muscle, there are other effects of HMB that may be beneficial to old people. HMB ameliorated the effects of ageing in the dendritic tree of the pyramidal neurons in the medial prefrontal cortex of both male and female rats and improved the working and cognitive flexibility in old-age rats.[74, 75] — ^[1]

Most of the quoted material above is already covered to some extent in the article at the moment, but the commentary from this review isn't reflected in the current article text. Should new content be added, or should this reference just be appended to existing text that it supports? Do any of you have any proposed revisions to the article in mind? @Doc James: I'm directing that last question mainly at you since you took issue with how some of the medical statements were worded during the most recent FAC nomination. Seppi333 (Insert 2¢) 04:27, 3 June 2017 (UTC)[reply]

2nd

A systematic review on β-hydroxy-β-methylbutyrate free acid supplementation suggests improvements in measures of muscle recovery, performance, and hypertrophy following resistance training

^[2]

@Boghog, Jytdog, and Doc James: The "#Upcoming systematic review" was finally published in an academic journal in September.^[2] Boghog, do you think we should renominate the article for FA or continue with GAN once I add coverage of this review and the other reviews listed below to the article? Seppi333 (Insert 2¢) 04:48, 9 November 2017 (UTC)[reply]

FYI: I'm waiting to get ref #5 below (PMID 28554316) from WP:RX before I update the article with the content from all of the reviews cited in this section (i.e., the ones in #Section reflist). Seppi333 (Insert 2¢) 01:13, 19 November 2017 (UTC)[reply]

3rd–8th

Pharmacological targeting of exercise adaptations in skeletal muscle: Benefits and pitfalls

^[3]

The Potential of β-Hydroxy-β-Methylbutyrate as a New Strategy for the Management of Sarcopenia and Sarcopenic Obesity

^[4]

Added

Beta-hydroxy-beta-methyl butyrate (HMB): From experimental data to clinical evidence in sarcopenia

^[5]

What factors influence protein synthesis and degradation in critical illness?

^[6]

~~Ergogenic Aids in Sports – February 2017 review (in Spanish - would probably only cite material covered in the abstract if this review is used).~~

^[7]

Efficacy and Safety of Leucine Supplementation in the Elderly

^[8]

Seppi333 (Insert 2¢) 05:19, 9 November 2017 (UTC) – Updated 06:12, 9 November 2017 (UTC)[reply]

Yes this ref says "Clinical trials performed in older adults confirm that HMB can attenuate the progression of sarcopenia in elderly subjects." So basically it may slow muscle loss.[6]

This review is a little more cautious concluding "However, heterogeneous methodological approaches preclude solid conclusions, and more studies are needed to confirm the role of HMB as a promising agent to treat sarcopenia."[7]

So definitely promising and appears safe but not yet definite. Doc James (talk · contribs · email) 05:44, 9 November 2017 (UTC)[reply]

@Doc James: I had to contact Dr. Alfonso Cruz-Jentoft via email to obtain his review article (i.e., the one that you mentioned was a little more cautious in your reply immediately above) since no one at WP:RX had access to the journal in which he published his review. You can read his review and its conclusions here. Seppi333 (Insert 2¢) 18:22, 17 December 2017 (UTC)[reply]

Quotation from PMID 28554316 about HMB's pharmacodynamics

- HMB increases myofibrillar protein synthesis by upregulation via the mTOR pathway.

- HMB modulates protein degradation by inhibiting the ubiquitin-proteasome proteolytic pathway in muscle cells. Ubiquitin is induced by immobilization and by catabolic conditions, inducing proteasome expression through the activation of nuclear factor kappa B (NK-κB), thus promoting muscle wasting. HMB may inhibit the activity of NK-κB, attenuating muscle loss in wasting conditions.

- The integrity of cell membranes depends on cholesterol synthesis from acetyl-CoA. HMB is converted to ß-hydroxyß- methylglutaryl-coenzyme A (HMG-CoA), which is turned into cholesterol by the HMG-coenzyme A reductase, the rate-limiting enzyme to cholesterol synthesis. Thus, HMB supplementation may stabilize cell membranes. HMB itself seems to be a component of cell membranes.

- HMB may prevent cell apoptosis and enhance muscle satellite cell survival.

- HMB increases proliferation and differentiation of muscle stem cells, via the MAPK/ERK and PI3K/Akt pathways.

- HMB up-regulates transcription and expression of the IGF-I gene in skeletal muscle and liver. IGF exerts an anabolic action and causes hypertrophy of skeletal muscle fibers.

Pharmacodynamics and pharmacokinetics of HMB-CA in humans in vivo

This is a primary source which examines the same pharmacodynamic and pharmacokinetic parameters for HMB-CA

the study on HMB-FA and leucine which is currently cited in the article

^[9]

Seppi333

Insert 2¢

06:12, 9 November 2017 (UTC)

[reply]

^[10]

Section reflist

References

^ ^a ^b ^c ^d ^e Holeček M (May 2017). "Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions". Journal of Cachexia, Sarcopenia and Muscle. 8 (4): 529–541. doi:10.1002/jcsm.12208. PMC 5566641. PMID 28493406.
^ ^a ^b Silva VR, Belozo FL, Micheletti TO, Conrado M, Stout JR, Pimentel GD, Gonzalez AM (September 2017). "β-hydroxy-β-methylbutyrate free acid supplementation may improve recovery and muscle adaptations after resistance training: a systematic review". Nutrition Research. 45: 1–9. doi:10.1016/j.nutres.2017.07.008. hdl:11449/170023. PMID 29037326. HMB's mechanisms of action are generally considered to relate to its effect on both muscle protein synthesis and muscle protein breakdown (Figure 1) [2, 3]. HMB appears to stimulate muscle protein synthesis through an up-regulation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), a signaling cascade involved in coordination of translation initiation of muscle protein synthesis [2, 4]. Additionally, HMB may have antagonistic effects on the ubiquitin–proteasome pathway, a system that degrades intracellular proteins [5, 6]. Evidence also suggests that HMB promotes myogenic proliferation, differentiation, and cell fusion [7]. ... Exogenous HMB-FA administration has shown to increase intramuscular anabolic signaling, stimulate muscle protein synthesis, and attenuate muscle protein breakdown in humans [2].
^ Weihrauch M, Handschin C (October 2017). "Pharmacological targeting of exercise adaptations in skeletal muscle: Benefits and pitfalls". Biochemical Pharmacology. 147: 211–220. doi:10.1016/j.bcp.2017.10.006. PMC 5850978. PMID 29061342.
^ Rossi AP, D'Introno A, Rubele S, Caliari C, Gattazzo S, Zoico E, Mazzali G, Fantin F, Zamboni M (October 2017). "The Potential of β-Hydroxy-β-Methylbutyrate as a New Strategy for the Management of Sarcopenia and Sarcopenic Obesity". Drugs & Aging. 34 (11): 833–840. doi:10.1007/s40266-017-0496-0. PMID 29086232. S2CID 4284897. Clinical trials performed in older adults confirm that HMB can attenuate the progression of sarcopenia in elderly subjects. HMB supplementation results in an increase in skeletal muscle mass and strength in the elderly and its effect is even greater when combined with physical exercise.
^ Cruz-Jentoft AJ (May 2017). "Beta-hydroxy-beta-methyl butyrate (HMB): From experimental data to clinical evidence in sarcopenia". Current Protein & Peptide Science. 18 (7): 668–672. doi:10.2174/1389203718666170529105026. PMID 28554316. HMB is widely used as an ergogenic supplement by young athletes.
^ Di Girolamo FG, Situlin R, Biolo G (March 2017). "What factors influence protein synthesis and degradation in critical illness?". Current Opinion in Clinical Nutrition and Metabolic Care. 20 (2): 124–130. doi:10.1097/MCO.0000000000000347. PMID 28002075. S2CID 3480306.
^ omitted - not planning to use this review
^ Borack MS, Volpi E (December 2016). "Efficacy and Safety of Leucine Supplementation in the Elderly". The Journal of Nutrition. 146 (12): 2625S–2629S. doi:10.3945/jn.116.230771. PMC 5118760. PMID 27934654. No serious side effects have been reported with leucine, EAA, or HMB supplementation; and the health risks associated with these supplements are few and predictable.
^ Wilkinson DJ, Hossain T, Limb MC, Phillips BE, Lund J, Williams JP, Brook MS, Cegielski J, Philp A, Ashcroft S, Rathmacher JA, Szewczyk NJ, Smith K, Atherton PJ (October 2017). "Impact of the calcium form of β-hydroxy-β-methylbutyrate upon human skeletal muscle protein metabolism". Clinical Nutrition (Edinburgh, Scotland). 37 (6): 2068–2075. doi:10.1016/j.clnu.2017.09.024. PMC 6295980. PMID 29097038. Ca-HMB led a significant and rapid (<60 min) peak in plasma HMB concentrations (483.6 ± 14.2 μM, p < 0.0001). This rise in plasma HMB was accompanied by increases in MPS (PA: 0.046 ± 0.004%/h, CaHMB: 0.072 ± 0.004%/h, p < [0.001]) and suppressions in MPB (PA: 7.6 ± 1.2 μmol Phe per leg min^-1, Ca-HMB: 5.2 ± 0.8 μmol Phe per leg min^-1, p < 0.01). ... During the first 2.5 h period we gathered postabsorptive/fasted measurements, the volunteers then consumed 3.42 g of Ca-HMB (equivalent to 2.74 g of FA-HMB) ... It may seem difficult for one to reconcile that acute provision of CaHMB, in the absence of exogenous nutrition (i.e. EAA's) and following an overnight fast, is still able to elicit a robust, perhaps near maximal stimulation of MPS, i.e. raising the question as to where the additional AA's substrates required for supporting this MPS response are coming from. It would appear that the AA's to support this response are derived from endogenous intracellular/plasma pools and/or protein breakdown (which will increase in fasted periods). ... To conclude, a large single oral dose (~3 g) of Ca-HMB robustly (near maximally) stimulates skeletal muscle anabolism, in the absence of additional nutrient intake; the anabolic effects of Ca-HMB are equivalent to FA-HMB, despite purported differences in bioavailability (Fig. 4).
^ Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ, Atherton PJ (June 2013). "Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism" (PDF). The Journal of Physiology. 591 (11): 2911–2923. doi:10.1113/jphysiol.2013.253203. PMC 3690694. PMID 23551944. The stimulation of MPS through mTORc1-signalling following HMB exposure is in agreement with pre-clinical studies (Eley et al. 2008). ... Furthermore, there was clear divergence in the amplitude of phosphorylation for 4EBP1 (at Thr37/46 and Ser65/Thr70) and p70S6K (Thr389) in response to both Leu and HMB, with the latter showing more pronounced and sustained phosphorylation. ... Nonetheless, as the overall MPS response was similar, this cellular signalling distinction did not translate into statistically distinguishable anabolic effects in our primary outcome measure of MPS. ... Interestingly, although orally supplied HMB produced no increase in plasma insulin, it caused a depression in MPB (−57%). Normally, postprandial decreases in MPB (of ~50%) are attributed to the nitrogen-sparing effects of insulin since clamping insulin at post-absorptive concentrations (5 μU ml⁻¹) while continuously infusing AAs (18 g h⁻¹) did not suppress MPB (Greenhaff et al. 2008), which is why we chose not to measure MPB in the Leu group, due to an anticipated hyperinsulinaemia (Fig. 3C). Thus, HMB reduces MPB in a fashion similar to, but independent of, insulin. These findings are in-line with reports of the anti-catabolic effects of HMB suppressing MPB in pre-clinical models, via attenuating proteasomal-mediated proteolysis in response to LPS (Eley et al. 2008).

GA review

Ongoing GA review

Reviewer: Tom (LT) (talk · contribs) 05:47, 28 November 2017 (UTC)[reply]

Out of sympathy for poor Seppi333 I will take up this review. I'll spend a few days familiarising myself with the subject matter and then post my review. --Tom (LT) (talk) 05:47, 28 November 2017 (UTC)[reply]

Thank you very much! – I really appreciate it Tom!! Seppi333 (Insert 2¢) 19:10, 28 November 2017 (UTC)[reply]

I forgot to mention, a lot of the paywalled reviews that are cited in this article can be viewed here: [8]. The file names for those papers reflect the reference names that are used in the article source (i.e., <ref name="xyz"> → xyz.pdf). Seppi333 (Insert 2¢) 21:44, 28 November 2017 (UTC)[reply]

As a note, I am reviewing this article here [9]. If this situation happens again, please ping me and I will review the article based on any changes in the interests of time. Also happy when this passes to participate at the FA if that helps. --Tom (LT) (talk) 07:37, 1 December 2017 (UTC)[reply]

Have made my first-pass review (and updated the table below). Will go through your replies and mark what has been addressed, and then when this is complete go through the article a second time and briefly as a second check. As stated above am happy to discuss anything below. --Tom (LT) (talk) 22:55, 8 December 2017 (UTC)[reply]

Assessment

Rate	Attribute	Review Comment
1. Well-written:
	1a. the prose is clear, concise, and understandable to an appropriately broad audience; spelling and grammar are correct.	~~Language is very technical and needs to be standardised. Presently quite difficult to read~~ significant work has been done to improve readability
	1b. it complies with the Manual of Style guidelines for lead sections, layout, words to watch, fiction, and list incorporation.
2. Verifiable with no original research:
	2a. it contains a list of all references (sources of information), presented in accordance with the layout style guideline.	~~I am concerned that the overuse of references, as stated below, makes this article hard to verify.~~ very well referenced
	2b. reliable sources are cited inline. All content that could reasonably be challenged, except for plot summaries and that which summarizes cited content elsewhere in the article, must be cited no later than the end of the paragraph (or line if the content is not in prose).	~~See discussion re. primary and small-scale sources below~~
	2c. it contains no original research.	All statements references
	2d. it contains no copyright violations or plagiarism.	None identified
3. Broad in its coverage:
	3a. it addresses the main aspects of the topic.
	3b. it stays focused on the topic without going into unnecessary detail (see summary style).	~~Several instances of acronyms and tidbits could be removed to enhance focus~~
	4. Neutral: it represents viewpoints fairly and without editorial bias, giving due weight to each.	Nil issues
	5. Stable: it does not change significantly from day to day because of an ongoing edit war or content dispute.
6. Illustrated, if possible, by media such as images, video, or audio:
	6a. media are tagged with their copyright statuses, and valid non-free use rationales are provided for non-free content.
	6b. media are relevant to the topic, and have suitable captions.	~~In the main, yes. One image being discussed below~~ Relevant images that add to the article
	7. Overall assessment.

Discussion

All right, Seppi333, I will be honest here. It's clear you've put a lot of work into this article and I'm sure published in a medical journal this would be an excellent review. However, it's published here on WP and is being reviewed for "GA status" which is a different kettle of fish.
Firstly though, even more confusingly for me as a reviewer:
1. (a) I can't seem to find a past GA review to compare my reviews against; and
2. (b) given this has been to FA a number of times I think it will be very frustrating if I provide all sorts of specific advice to you which then needs to be rechanged in accordance with the FA reviewers' opinions; and
3. (c) some of the issues I raise are probably in response to the concerns of others.
That said, I've reviewed probably more than 80 articles, including some complex ones, so I think I have a fair idea of how to interpret GA criteria. So, here goes:
In general, I find this article very hard to read. I find this difficult for a few reasons. There are a lot of references everywhere, and a lot of wikilinks. The language is very technical. I find some of the paragraphs could be arranged in a better way. A lot of facts are presented at once without much synthesis. Systematic reviews are placed beside primary sources. Language used to describe similar issues is inconsistent. Also in some areas extraneous information provided that could be cut to make things easier to read.
Now, taking into account (a)-(c), I'm not quite sure what to do. I can pass this article given there doesn't seem to be many others who have commented about the readability of the article in past FA reviewers, and let FA reviewers nut out the details. I could ask for a second reviewer (not inclined to do this). I could provide specific advice which is likely to be fairly subjective. What do you think/want, Seppi333? --Tom (LT) (talk) 23:06, 2 December 2017 (UTC)[reply]
@Tom (LT): I'd prefer your specific advice on how to improve the readability (alternatively, feel free to make any changes you see fit it if you feel comfortable with it). If we end up rewriting the entire article in the process, that's fine with me as long as there's an improvement. Anyway, this is the first GA review for this article since I initially decided to skip the GA process and go straight to FAC. Seppi333 (Insert 2¢) 00:29, 3 December 2017 (UTC)[reply]

OK, here goes then:--Tom (LT) (talk) 22:30, 3 December 2017 (UTC)[reply]

@Tom (LT): I finished going through the points below. I just need your feedback on my responses about some of the statements in the medical and pharmacodynamics sections in order to proceed with addressing those issues. Seppi333 (Insert 2¢) 23:12, 21 December 2017 (UTC)[reply]

Review of text

Happy to discuss any of the below. These suggestions are not intended to be prescriptive & only intended to illustrate my concerns about the 'well-written' point. They don't all need to be addressed for the review to pass. Hope it is helpful. --Tom (LT) (talk) 22:59, 3 December 2017 (UTC)[reply]

I'll address these issues as time permits. I'm not addressing these points in any systematic order, so it might appear that I've ignored some of them until I get to them. Seppi333 (Insert 2¢) 20:24, 4 December 2017 (UTC)[reply]

Lead

Addressed

Too many citations. Referring to previous consensus, I have no issue with citations in the lead. However surely as a summary of text these could be whittled down to your main citations, and the lists can be provided in text.
- Fixed with sources notes. If you have an alternative solution in mind, please let me know. Seppi333 (Insert 2¢) 19:25, 13 December 2017 (UTC)[reply]
- ~~In progress~~: I'll work on pruning some of the citations in the lead's "sources" notes this weekend when I work on reducing the citations for content in the body. I've removed 1 so far and have identified a 2nd that I intend to remove tomorrow when I update the body of the article. Seppi333 (Insert 2¢) 02:34, 16 December 2017 (UTC)[reply]
  - Done: Since 2 days ago, I cut 2 refs from the first note, which has the most refs among the 3 lead sources notes. I can't cut anymore refs without affecting the lead's verifiability. Seppi333 (Insert 2¢) 21:58, 17 December 2017 (UTC)[reply]
    - Thanks. --Tom (LT) (talk) 23:11, 17 December 2017 (UTC)[reply]
Suggest revise statement about use so that it flows in a logical order adults -> older adults and certain statements -> uncertain statements
- All of the sentences in the lead now contain only statements of certainty; the only one that includes a clause with an a statement about effects which are uncertain is "HMB can reduce the loss of lean body mass in individuals experiencing age-related muscle loss, but more research is needed to determine how it affects muscle strength and function in older adults." The preceding sentence was recently updated with a statement of certainty about the effect on muscle strength in this age group. ~~I could move that statement down if you still want me to; however, it should be noted that,~~ After moving the statement you mentioned in the bullet below, the current ordering of the sentences in the 1st lead paragraph reflects the same order of content coverage as the body. I'm think Doc James might object at the next FAC to ordering medical uses after performance-enhancing uses in the lead; but, if he's okay with that, I'll put it in that order as you suggest. Seppi333 (Insert 2¢) 06:51, 8 December 2017 (UTC)[reply]
  - @Doc James: Would you mind if I reordered the statements in the 1st lead paragraph as suggested above? Seppi333 (Insert 2¢) 06:55, 8 December 2017 (UTC)[reply]
    - Not putting the refs behind the sentence they support IMO is not an improvement. Having them as a block of 13 makes it impossible for me to determine which part of the lead is supported by which reference.
    - I see that they are now hidden comments but I would simple show them.
    - If athletic uses are more common, I do not have an issue with that use going first in the first paragraph. Doc James (talk · contribs · email) 18:19, 8 December 2017 (UTC)[reply]
      - @Doc James: It's already in the lead; my question was if you would object me be reversing the order of the sentences ~~in the collapse tab below (these sentences summarize its medical and performance-enhancing uses)~~ (edit: I've deleted the collapse tab and the content inside since it took up a lot of space in the source). Seppi333 (Insert 2¢) 19:59, 8 December 2017 (UTC); Updated 02:33, 16 December 2017 (UTC)[reply]
        @Tom (LT): Done: I ordered the statements on clinical effects in the lead as you suggested (healthy adults, then older adults) since Doc James didn't object following my ping (this edit was made in this diff). I removed the statement about more research being needed in an earlier edit, so there's currently no statements on uncertain effects in the lead. If you have any other suggestions for ordering the 1st lead paragraph, I'm still open to modifying it though. Seppi333 (Insert 2¢) 19:24, 13 December 2017 (UTC)[reply]
        Thanks. --Tom (LT) (talk) 23:11, 17 December 2017 (UTC)[reply]
Suggest move statement "It is added to certain medical foods that are intended to provide nutritional support for people with muscle wasting due to cancer or HIV/AIDS and to promote wound healing." up to where you discuss clinical uses
- Done: it's now located immediately after the 1st lead sentence. Seppi333 (Insert 2¢) 19:24, 13 December 2017 (UTC)[reply]

@Tom (LT): Re: The lead references – Do you want me to use the same referencing style that was used in the lead of amphetamine? Seppi333 (Insert 2¢) 20:51, 4 December 2017 (UTC)[reply]

@Tom (LT): Nevermind, I went ahead and did redid the lead sources analogous to amphetamine's lead. I'm going to group the sources in the body in the same manner as is done in the amphetamine article (sentences with 4+ references have their references placed in a sources note). Do you approve of that approach? Seppi333 (Insert 2¢) 04:38, 8 December 2017 (UTC)[reply]

@Seppi333, Doc James. No bright suggestions for references in lead other than to (1) restate the lead is very difficult to read with so many references interspersed between text and (2) agree with you Doc James that large groups of references are hard to verify.--Tom (LT) (talk) 22:57, 8 December 2017 (UTC)[reply]

I'm not really sure how else to address this problem without using the ^{[sources #]} notes and censored refs for the sentences. Most of the lead sentences are either summaries of 2+ sentences in the body that are supported piece-wise by different references or exact duplicates of sentences in the body that (IMO) require multiple refs for making significant medical claims on efficacy/safety. Seppi333 (Insert 2¢) 19:31, 13 December 2017 (UTC)[reply]

We've done what we can, I won't push this point further. Thanks for responding to my concerns --Tom (LT) (talk) 23:11, 17 December 2017 (UTC)[reply]

Suggest remove unnecesssary acronyms, including WADA and NCAA which are only used once Done

Uses

Medical

Does this article ("Elderly persons with ICU-acquired weakness: the potential role for β-hydroxy-β-methylbutyrate (HMB) supplementation") really comment on HIV immune function? (it is used here "Clinical trials with Juven for AIDS")
- Yes. From [10]: In patients with human immunodeficiency virus (HIV), Clark et al46 have demonstrated that HMB supplementation in addition to arginine and glutamine not only increased lean body mass by 2.6 kg but also increased CD3, CD4, and CD5 cell counts. As noted above, the full-text of paywalled citations in this article can be accessed via this link: [11]. The file names of the pdf files are the same as the reference names that are used in the article source (i.e., <ref name="xyz"> → xyz.pdf). Seppi333 (Insert 2¢) 05:30, 8 December 2017 (UTC)[reply]
  - Right. This study is just referencing another primary source. I strongly advocate we remove this. I don't think it's responsible to insert a statement like this without a stronger source. --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)[reply]
    - I'm confused. PMID 24072740 is marked as a review on Pubmed; the quote from above is just a summary of 1 of the primary sources it reviewed. I can check whether or not that primary source is covered in one of the other medical reviews I've cited if that's what you're asking about though. Seppi333 (Insert 2¢) 22:48, 12 December 2017 (UTC)[reply]
      - The source that this statement is derived from is a primary source. I really don't think we should be including something like this, which is a medical claim unless there is a stronger source (WP:MEDRS). It is in my mind misleading to state that HMB has a role in HIV/AIDS management without stronger evidence. --Tom (LT) (talk) 02:36, 15 December 2017 (UTC)[reply]

Like I was saying before, that statement is cited and supported by PMID 24057808 and PMID 24072740, both of which are classified as a medical reviews on Pubmed (follow the PMID links and click/expand the tab titled "Publication type, MeSH terms, Substances" – doing this will display "Publication type: Review"). The quoted sentence above in my initial reply to this bullet – "In patients with human immunodeficiency virus (HIV), Clark et al46 have demonstrated that HMB supplementation in addition to arginine and glutamine not only increased lean body mass by 2.6 kg but also increased CD3, CD4, and CD5 cell counts" – is from the 2nd review that I've listed (i.e., PMID 24072740), not the primary source it was reviewing. In other words, that statement isn't cited or supported by a primary source; rather, it's cited and supported by 2 medical reviews which covered the findings of PMID 10850936, which is a primary source that you seem to be confusing the review with. That primary source is not currently and has never been cited in this article. In any event, if you'd prefer that I use a newer review instead, I can cite a medical review from 2017 (PMID 28493406 - see Table 6 from this review) which includes 2 clinical trials with HMB for AIDS. On a slightly tangential note, HMB is currently included in medical foods that are used to provide nutritional support in individuals with AIDS/HIV (NB: medical foods are intended to be taken under medical supervision in the United States – see pages 3–6 of this FDA guidance document for further information on their regulatory/labeling requirements). Seppi333 (Insert 2¢) 01:03, 16 December 2017 (UTC)[reply]

@Tom (LT): Sorry, it just occurred to me that you seem to be taking issue with covering the findings from reviews that included that particular clinical trial in the article, not the reviews themselves. If I'm correct about that being the issue here, then when you say "a stronger source", do you mean we should wait until a 2nd clinical trial that examines those parameters is published and subsequently reviewed? Right now, there's 3 reviews that cover 2 clinical trials of HMB for AIDS, but only 1 of those trials examined CD3 and CD8 counts. In the event you'd like to read about what clinical parameters the 2nd trial examined, this is a link to its full text: {{DOI|10.1177/014860710402800265}}. If you can clarify what the issue is, I'd appreciate it, since I'm not sure if you're asking for a replacement review of that trial (re: my previous reply) or a review of a corroborating trial/primary source (re: this reply). Seppi333 (Insert 2¢) 01:21, 16 December 2017 (UTC)[reply]

The two issues are: the sentence states "Clinical trials with Juven for AIDS have also demonstrated improvements in immune status, as measured by a reduced HIV viral load relative to controls and higher CD3+ and CD8+ cell counts". (a) Here it states "trialS" yet there as you say there is only one trial showing reduced HIV viral load. (b) given that there is only one trial, it really is just included, not supported, by the reviews. I would be happy if this was rephrased in a more general way, or if the second clause was removed. --Tom (LT) (talk) 01:23, 19 December 2017 (UTC)[reply]
- I've changed the plural to singular to accurately reflect this (diff). I don't think it would be wise to delete this sentence. While these findings are from 1 study which was included in these reviews, these endpoints were specifically mentioned in the text of the review articles despite not being the primary endpoint (which was a change in lean mass) in the study itself. I.e., the authors probably discussed these secondary endpoints because they are notable in their own right. In any event, what phrasing did you have it mind for this sentence? Seppi333 (Insert 2¢) 01:26, 20 December 2017 (UTC)[reply]

"The efficacy of Juven for the treatment of cancer cachexia was also examined in a phase 3 clinical trial which found a strong trend (i.e., p=.08) for an improvement in lean body mass relative to controls;[14][30][33] however, according to the authors of the trial itself and a systematic review that included it, the trial did not adequately test the ability of Juven to prevent or reverse the loss of lean body mass in individuals with cancer cachexia since the majority of participants did not complete the study" I do not believe a phase 3 study meets WP:MEDRS. Surely it is a primary source. You then even include criticism by a systematic review. Should this be included at all?
- The assertion which was made in the systematic review about the clinical trial is identical to the assertion made by the authors of clinical trial publication. In other words, the clinical trial source and systematic review draw the same conclusion about the clinical trial. I'll remove that primary source if you think it detracts from the article; I only added it because I thought it helped to show consensus. Seppi333 (Insert 2¢) 05:30, 8 December 2017 (UTC) Removed + rephrased sentence[reply]
  - I think that, guided by our local policy WP:MEDRS, we treat the secondary source as having more weight and should remove the primary phase three trial. --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)[reply]
    - Sorry, I should've clarified that the thing I removed earlier was that primary source - it's no longer cited in the article (diff of removal). I rephrased the sentence after I removed it because the sentence stated something along the lines of: "the authors of the trial and a systematic review that included it stated..." Seppi333 (Insert 2¢) 22:48, 12 December 2017 (UTC)[reply]
      - Thanks. The line at issue is still present? "The efficacy of Juven for the treatment of cancer cachexia was also examined in a phase 3 clinical trial which found a strong trend (i.e., p=.08) for an improvement in lean body mass relative to controls" --Tom (LT) (talk) 23:31, 17 December 2017 (UTC)[reply]
        What's wrong with that sentence? Seppi333 (Insert 2¢) 01:07, 20 December 2017 (UTC)[reply]
  NB: The only reason I've included any primary medical sources in this article is to support existing medical reviews or to supplement medical reviews which don't cover specific details that are only covered in the primary source. E.g., the specific mechanisms of action that give rise to HMB's mode of action aren't covered in most medical reviews, and those that do mention mechanisms of action gloss over the details; in contrast, HMB's mode of action (increased protein biosynthesis and reduced protein catabolism) is covered in almost every medical review about the compound. Seppi333 (Insert 2¢) 05:30, 8 December 2017 (UTC)[reply]

Addressed

So many citations. Are all of these needed??
- For statements that contain clinically significant medical claims, yes. I don't think it's adequate to support a statement of a dietary supplement's clinical efficacy with a single citation since many claims about the efficacy of dietary supplements for any particular condition or effect are dubious. One can probably find a source to support a statement of efficacy for most dietary supplements for a particular purpose, so showing that there's scientific consensus across multiple reviews by citing more than one is, IMO, both appropriate and necessary in this context. This approach is followed for statements about this compound's safety profile as well. Moreover, for a number of sentences in the article, the statement requires multiple sources because it makes multiple non-medical claims that are only individually supported by the cited references (i.e., a sentences with 3 claims might be supported by 3 sources, where each source supports only 1 of the claims). Seppi333 (Insert 2¢) 05:30, 8 December 2017 (UTC)[reply]
- As I see below, sometimes what may be seen as one point is in fact two or three. On the other hand, if at all possible for a noncontroversial statement, it is adequate to use a reliable secondary source. The large number of references shows how much effort has been put into this article but also makes it harder to read and verify. So trimming if possible would be appreciated. --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)[reply]
  - ~~In progress~~: I'll work on cutting down the number where possible and appropriate. I'll work on pruning the refs in this section and any corresponding ones in the lead sometime this weekend. Seppi333 (Insert 2¢) 03:19, 16 December 2017 (UTC)[reply]
    - Done: I removed a review that wasn't really necessary in this diff. As of now, I've cut at least 2 references (that I remember) from this section: this review and the phase 3 clinical trial. I'm not sure it would be wise to cut reviews on the efficacy statements, which are the only statements in the text which still have multiple (i.e., 2 or 3) citations for the same content. Seppi333 (Insert 2¢) 23:05, 21 December 2017 (UTC)[reply]
      - Thanks. --Tom (LT) (talk) 22:21, 25 December 2017 (UTC)[reply]
Second paragraph is confusing because it alternates rapidly between sarcopenia, muscle mass, lean muscle mass, muscle weight , muscle atrophy, muscle wasting... if possible it would be good if these terms could be standardised into more consistent terms for ease of reading (eg "sarcopenia -> skeletal muscle mass; muscle weight/mass -> muscle mass; muscle atrophy/wasting -> loss of muscle mass")
- ~~( In progress)~~ I've revised it slightly. I'll try reworking it a little more later. I agree that it does alternate a bit too much. Seppi333 (Insert 2¢) 07:04, 8 December 2017 (UTC)[reply]
  - Done: I went back through it and added links to bed rest and muscle atrophy. I don't think it would be wise to change sarcopenia and/or muscle atrophy to "the loss of skeletal muscle mass" because these two terms specify a cause for this effect: sarcopenia is a medical condition involving the loss of muscle mass due to old age, whereas muscle atrophy is a condition involving the loss of muscle mass use to disuse of a muscle. If you think it should be further modified, let me know. Seppi333 (Insert 2¢) 22:57, 21 December 2017 (UTC)[reply]
    - Thanks, your changes are noted :) --Tom (LT) (talk) 22:21, 25 December 2017 (UTC)[reply]
Suggest that the whole section be reworded and possibly split up into the following: (1) preserving muscle mass in hypercatabolic states (2) preserving muscle mass in aging (3) other uses; and restrucrigin paragraphs so that the proceed as in (a) findings followed by (b) details at end of paragraph.
- In progress: I'll look into doing this ~~tomorrow~~ soon and follow up then. Seppi333 (Insert 2¢) 07:09, 8 December 2017 (UTC)[reply]
  - Revised the section: I grouped the material as follows in this diff: statements about HMB for sarcopenia; statements about HMB for muscle atrophy from bed rest; statements about HMB for hypercatabolic disease states; and, recommendations from reviews on the treatment of all of the aforementioned conditions. If you think I should further revise it, let me know. Seppi333 (Insert 2¢) 22:57, 21 December 2017 (UTC)[reply]
  - Thanks, the paragraph is much easier to read. --Tom (LT) (talk) 22:21, 25 December 2017 (UTC)[reply]

Available forms

Ensure and Juven aren't linked Done

"Investigation of the presence of β-hydroxy-β-methylbutyric acid and α-hydroxyisocaproic acid in bovine whole milk and fermented dairy products by a validated liquid chromatography-mass spectrometry method" - does not seem like a secondary source
- It's a primary source; however, the statement "[HMB] is present in insignificant quantities in certain foods, such as alfalfa, asparagus, avocados, cauliflower, grapefruit, catfish, and milk" is not a medical statement. That primary source supports only its presence in bovine milk. HMB is also present in human breast milk, but that wasn't mentioned in that sentence. It is, however, covered more in depth in the "Detection in body fluids" section: In the breast milk of healthy lactating women, HMB and l-leucine have been quantified in ranges of 42–164 μg/L and 2.1–88.5 mg/L.[15] In comparison, HMB has been detected and quantified in the milk of healthy cows at a concentration of <20–29 μg/L.[22] This concentration is far too low to be an adequate dietary source of HMB, but milk products could be fortified with HMB to confer benefits to skeletal muscle.[22] If you think that I should remove the mention of milk and the primary source from sentence anyway, I'm ok with doing that. Seppi333 (Insert 2¢) 20:48, 4 December 2017 (UTC)[reply]
  - Thanks for your reply, I understand that. I also note that the non MEDMOS (WP:SECONDARY) also states it is not ideal to use a primary source. I would be inclined to remove it or replace it with a better source. --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)[reply]
    - Alright, I'll look for an alternative reference. ~~In progress~~ Seppi333 (Insert 2¢) 22:48, 12 December 2017 (UTC)[reply]
      - Removed: I couldn't find an alternative one, so I deleted the ref and mention of milk in the lead and available forms section (diff). Do you want me to delete the reference and the 2 sentences that it cites in the Beta-Hydroxy beta-methylbutyric acid#Detection in body fluids section as well (1st paragraph - last 2 sentences)? That's the only section where that the reference is cited at the moment. Seppi333 (Insert 2¢) 07:19, 13 December 2017 (UTC)[reply]
        Thanks. Am happy with the new arrangement. --Tom (LT) (talk) 23:22, 17 December 2017 (UTC)[reply]
Number of citations here is even less for the same statements than the lead
- (see point below for this) --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)[reply]
"when taken in doses of 3 grams per day" you say "3-6 grams" in the lead
- The listed dollar amount and citation applies to 3 grams/day; the reader can probably figure out how much 6 grams would cost from the listed range though Seppi333 (Insert 2¢) 20:13, 4 December 2017 (UTC)[reply]
  - Heh, I realise that. I just mean that the lead seems to be more than just a summary of the body in this instance ("Apart from basic facts, significant information should not appear in the lead if it is not covered in the remainder of the article.", WP:LEAD), so I think this information should be included in the body too. --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)[reply]
    - In progress: Oh, haha. Ok, I can add it. Will do it the next time I work on the article. Seppi333 (Insert 2¢) 22:48, 12 December 2017 (UTC)[reply]
      - Added in this diff. Seppi333 (Insert 2¢) 06:57, 13 December 2017 (UTC)[reply]
        Thanks. --Tom (LT) (talk) 23:22, 17 December 2017 (UTC)[reply]

Medical

"More research is needed." Does this need to be stated? This can surely be stated about almost everything.
- ~~This is stated twice; are you referring to one or both statements? The reason it was included w.r.t. the sarcopenia statement is that it was stated as a conclusion of the meta-analysis.~~ Seppi333 (Insert 2¢) 07:04, 8 December 2017 (UTC)[reply]
- The reason it was stated in the bed rest-associated muscle atrophy sentence is that there is preliminary evidence from clinical trials with small sample sized for efficacy, but its treatment efficacy hasn't been well-established based upon phase 3 randomized controlled trials (i.e., clinical trials with rather large sample sizes), as is required for FDA-approved medications. Seppi333 (Insert 2¢) 20:35, 4 December 2017 (UTC)[reply]
- I've removed both instances where "more research is needed" was stated in this section. The first instance of that statement in the sentence about muscle strength in sarcopenic adults was removed when I updated the text with a medical review from 2017; that review made a conclusive statement about HMB's effect on muscle strength in sarcopenic adults based upon more recent primary research. The second instance of that statement in the sentence on bed rest was removed when I rephrased the sentence as: Preliminary clinical evidence suggests that HMB supplementation may also prevent muscle atrophy during bed rest (diff). I think that wording conveys the same meaning as the original wording about more research being needed to establish efficacy. Seppi333 (Insert 2¢) 01:32, 16 December 2017 (UTC)[reply]

Enhancing performance

Are four citations really needed for this sentence "HMB produces these effects..."?
- No, all of it is supported by just 1 reference, but it is a significant medical claim since it states a mechanism responsible for the clinical effects. I placed the references supporting that sentence into a sources note since there were 4, but do you want me to prune it down anyway? Seppi333 (Insert 2¢) 22:27, 12 December 2017 (UTC)[reply]
  - I think if possible, for ease of verification, and I do not think that this is particularly controversial, you could include the best of these references, or at the most 2. 4 is excessive. --Tom (LT) (talk) 02:36, 15 December 2017 (UTC)[reply]
    - ~~In progress~~: Alright, I'll reduce it to 2 the next time I update the article. That should cut at least 1 ref from the first lead paragraph's "sources" note. I removed 1 ref from the 1st lead paragraph's sources note earlier when I updated the safety profile statement as well. Seppi333 (Insert 2¢) 02:41, 16 December 2017 (UTC)[reply]
      - Done: it's now cited by only 2 of the 4 refs. Seppi333 (Insert 2¢) 20:45, 17 December 2017 (UTC)[reply]
        Thanks. --Tom (LT) (talk) 23:09, 17 December 2017 (UTC)[reply]
"Untrained individuals and trained athletes" seems to cover the whole spectrum of people doing exercise?
- I've modified to the clause to specify untrained individuals and athletes who perform high intensity resistance or aerobic exercise. Moderate exercise causes high levels of muscular stress in untrained individuals, but that typically only occur at high intensities in trained individuals. Seppi333 (Insert 2¢) 22:27, 12 December 2017 (UTC)[reply]
  - Thanks. Question: This sentence seems to have only two factual statements. Does it need three references? --Tom (LT) (talk) 02:36, 15 December 2017 (UTC)[reply]
    - The phrase "these effects" refers to the 8 effects of HMB (muscle hypertrophy/strength/power, lean mass, muscle damage, exercise recovery, aerobic exercise performance, and aerobic fitness) that were stated in the 2 sentences which preceded this sentence. Those 2 sentences were supported by 6 reviews. This statement could be fully supported by 2 reviews if I deleted the preceding sentence on HMB's effects on aerobic exercise performance and aerobic fitness, but I don't think it would be wise to do so. The third review is necessary for supporting that part. Do you want me to cut the preceding sentence and remove the third review from this sentence, or should I clarify that the phrase "these effects" refers to the aforementioned effects on skeletal muscle and aerobic performance/fitness? Seppi333 (Insert 2¢) 01:56, 16 December 2017 (UTC)[reply]
      - OK, fair enough. No issues there. --Tom (LT) (talk) 23:09, 17 December 2017 (UTC)[reply]
"The inhibition of exercise-induced skeletal muscle damage by HMB is affected by the time that it is used relative to exercise" (1) does this need two references? (2) I have no bright ideas but I'm sure this sentence could be written in a simpler manner
- I'll think about how to rephrase the sentence. ~~In progress~~
  - Done – rephrased as "The efficacy of HMB supplementation for reducing skeletal muscle damage from prolonged or high-intensity exercise is affected by the time that it is used relative to exercise." Let me you if you think it needs further revision. Seppi333 (Insert 2¢) 07:16, 14 December 2017 (UTC)[reply]
    - Reads much better, thanks. --Tom (LT) (talk) 02:36, 15 December 2017 (UTC)[reply]
- ~~It doesn't need two references. Should it have only 1?~~ Actually, since this sentence is discussing efficacy, I think it would be better to leave it as is. Seppi333 (Insert 2¢) 22:27, 12 December 2017 (UTC)[reply]
  - I think for ease of verification, and given that this does not seem to be a particularly controversial statement, the better of the two references should be included only. (but happy to compromise on this - I will flag it in the FA review if you want to leave it) --Tom (LT) (talk) 02:36, 15 December 2017 (UTC)[reply]
    - I've removed the 2nd review which supported that sentence (see this diff for the removal). Seppi333 (Insert 2¢) 01:39, 16 December 2017 (UTC)[reply]
      - Thanks. --Tom (LT) (talk) 23:09, 17 December 2017 (UTC)[reply]
Suggest move "dose dependently" to a separate sentence
- I deleted "dose-dependently" and indicated a specific dose that the vast majority of HMB studies have used instead ("3 grams of HMB per day"). Seppi333 (Insert 2¢) 22:27, 12 December 2017 (UTC)[reply]
In this sentence "When combined with" there are only 4 references used more than 10 times. I suggest either trim, move to end of sentence, or hide the references mid sentence using comments
- Done – I moved the refs to the end of the sentence and placed them in a sources note; I also hid them where they were to support WP:V. Seppi333 (Insert 2¢) 18:31, 12 December 2017 (UTC)[reply]
  - Thanks. --Tom (LT) (talk) 22:00, 12 December 2017 (UTC)[reply]
Is quite technical to read. Suggest some changes such as "When combined with" -> "With", "augments" -> "adds to"; "expedite" -> "speed up" Done

Side-effects

Addressed

Could include information about what happens if more than the stated doses are taken?
- Experiments in animals with very high doses uses didn't indicate any and to my knowledge there is no reported median lethal dose (LD₅₀) for this compound. Clinical research in humans hasn't indicated any adverse effects from higher doses (IIRC, up to 15 grams/day has been used before without reported side effects in a small study, but I don't remember where I read that). Based upon the hypothesized immediate targets of this compound, it seems unlikely that this compound would be capable of exerting an acute toxic from high doses via pharmacological means since, beyond a certain dose (presumably in the 3-6 gram range), its effect on signaling cascades is saturated since the activation of each protein in the cascades that it triggers is already maximal. Most studies use 3 grams of HMB because there's little difference in clinical efficacy from taking 3 grams vs 6 grams, not because of the potential for adverse effects. It is possible that biotransformation of large amounts of HMB to HMB-CoA could produce adverse effects if, for some reason, one or both of the two other primary metabolic pathways of HMB-CoA are inhibited (HMB-CoA→MC-CoA and HMB-CoA→HMG-CoA), based upon a primary study (see reference quote);^[1] however, healthy individuals are capable of readily converting HMB-CoA to MC-CoA or HMG-CoA, which are subsequently metabolized into other compounds like cholesterol and ketones, among others. Seppi333 (Insert 2¢) 20:06, 13 December 2017 (UTC)[reply]
  - Interesting. I think it is useful in pharmacological articles to note something about overdose/ the unlikely possibility of overdose.--Tom (LT) (talk) 23:16, 14 December 2017 (UTC)[reply]
    - ~~In progress~~: I'll go back through the cited reviews in this section to see what they say about HMB overdose/toxicity; if I can, I'll add a statement about HMB overdose in the article. Seppi333 (Insert 2¢) 02:04, 16 December 2017 (UTC)[reply]
      - ~~The only review that commented on fairly high dose usage was the one that reviewed animal studies involving HMB.~~ It stated, The no-observed adverse-effect level (NOAEL) was determined to be 3.49 and 4.16 g/kg BW daily for male and female rats, respectively". I don't think this would be particularly useful to include in the article, because an equivalent dosing in humans must first be converted using a predetermined scaling metric which isn't mentioned in the review (see the USFDA's guidance on this). In other words, since a human equivalent dose is not specified by this review, stating those g/kg values in rats would be misleading since they'll probably be interpreted by some readers as applying to humans. Nevermind, the newest review that I recently added mentioned the equivalent dose for humans based upon the same study. It stated: "One study tested the safety of HMB for long-term use in rats. Fuller et al. (50) conducted a 91-d study with the use of Sprague-Dawley rats that tested the safety of b-hydroxy-b-methylbutyric free acid (HMBFA). This new form of HMB results in higher HMB serum concentrations than CaHMB. In this study, rats were administered an HMBFA intervention of 0%, 0.8%, 1.6%, or 4% of the diet by body weight. The highest dose is the equivalent of ~400 mg * kg^-1 * d^-1 for humans. No adverse advents were observed for any treatment group. Similarly, blood and urine analyses were within the normal range in all groups, with no group differences. The authors concluded that HMBFA was safe for consumption in a rat model." Seppi333 (Insert 2¢) 01:38, 20 December 2017 (UTC); Updated/edited at 05:46, 20 December 2017 (UTC)[reply]
        Added in this diff. Seppi333 (Insert 2¢) 06:23, 20 December 2017 (UTC)[reply]

In general easy to understand and well-written.
- Glad to hear. This section was the subject of a lot of editorial feedback/revision in an earlier talk page discussion (Talk:Beta-Hydroxy beta-methylbutyric acid#Comment about safety). Seppi333 (Insert 2¢) 20:06, 13 December 2017 (UTC)[reply]
The safety profile - four references needed for that statement?
- It could be cited and fully supported by only 2 (1 review on clinical research in humans, 1 review on animal research), but the additional 2 references were included to demonstrate that there is scientific consensus about its safety profile across several independent medical reviews of clinical research. Seppi333 (Insert 2¢) 20:06, 13 December 2017 (UTC)[reply]
  - I think that for the section, or even for the inclusion of specific side-effects, these references may be needed. But to support the statement "The safety profile of HMB in adult humans is based upon evidence from clinical trials in humans and animal studies", which is almost in WP:SKYISBLUE territory, four is too many. --Tom (LT) (talk) 23:16, 14 December 2017 (UTC)[reply]
    - Done: I've replaced 1 review with a newer one and deleted 2 reviews which supported that statement. It's now cited by only 2 reviews. Seppi333 (Insert 2¢) 02:13, 16 December 2017 (UTC)[reply]
    - Also, I've updated (reduced) the number of corresponding references in the lead. Seppi333 (Insert 2¢) 02:28, 16 December 2017 (UTC)[reply]

References

^ Mock DM, Stratton SL, Horvath TD, Bogusiewicz A, Matthews NI, Henrich CL, Dawson AM, Spencer HJ, Owen SN, Boysen G, Moran JH (November 2011). "Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans". The Journal of Nutrition. 141 (11): 1925–1930. doi:10.3945/jn.111.146126. PMC 3192457. PMID 21918059. Reduced activity of MCC impairs catalysis of an essential step in the mitochondrial catabolism of the BCAA leucine. Metabolic impairment diverts methylcrotonyl CoA to 3-hydroxyisovaleryl CoA in a reaction catalyzed by enoyl-CoA hydratase (22, 23). 3-Hydroxyisovaleryl CoA accumulation can inhibit cellular respiration either directly or via effects on the ratios of acyl CoA:free CoA if further metabolism and detoxification of 3-hydroxyisovaleryl CoA does not occur (22). The transfer to carnitine by 4 carnitine acyl-CoA transferases distributed in subcellular compartments likely serves as an important reservoir for acyl moieties (39–41). 3-Hydroxyisovaleryl CoA is likely detoxified by carnitine acetyltransferase producing 3HIA-carnitine, which is transported across the inner mitochondrial membrane (and hence effectively out of the mitochondria) via carnitine-acylcarnitine translocase (39). 3HIA-carnitine is thought to be either directly deacylated by a hydrolase to 3HIA or to undergo a second CoA exchange to again form 3-hydroxyisovaleryl CoA followed by release of 3HIA and free CoA by a thioesterase.

Pharmacology

Addressed

Pharmacodynamics

If possible would suggest "protein synthesis" -> "protein creation" or even "formation" (and standardise "biosynthesis")
- The terms "muscle protein synthesis" (MPS) and "muscle protein breakdown" (MPB) are widely used in the literature on this compound and on muscle protein turnover in general. I'll simplify the phrase if you really think it should be rephrased; but, at the same time, I'd expect the average high school student to know what the term "synthesis" means since most high schools require students to learn chemistry and biology. Seppi333 (Insert 2¢) 21:45, 13 December 2017 (UTC)[reply]
  - I will demure on this point, but it is just an example of how this article could be made easier to read for the lay person. To support my assertion, I quickly calculated a Flesch Grade Level on this article using MS word, and it is 19.5, ie. suitable for reading by those with more than 6 years of university education. The average US adult reads at grade 8-9. --Tom (LT) (talk) 01:27, 19 December 2017 (UTC)[reply]
    - The pharmacodynamics and chemistry sections of a drug article are not interesting to most people who read a drug article (e.g., I've completely rewritten a few drug articles and the chemistry section still doesn't interest me that much; the synthesis section in drug articles is gibberish to me because I lack the necessary background knowledge in organic chemistry to interpret it). They're both very specialized topics that should be included in pharmacology articles, but which necessary involve a lot of fairly technical material. If someone isn't familiar with molecular biology and pharmacology, they're not going to understand a comprehensive pharmacodynamics section – regardless of how simplistic the language is – because they lack a background knowledge of important concepts; for example, in this article, this section isn't going to make sense to anyone who isn't familiar with what signaling cascades, ribosomes, and proteasomes are and their purpose in cells. One way of addressing this is by adding notes to sentences to clarify what is being discussed and elaborate on those concepts (e.g., like this note, this one, or this third one), but I haven't done this in this article (yet). Let me know if you think it's worth clarifying some of the concepts in this section with explanatory notes; I'm willing to do that. Dumbing down the language in the entire section probably won't make it more readable without addressing this other issue though. If there are particular sentences that you think should be clarified in this section, please point them out! Seppi333 (Insert 2¢) 01:51, 20 December 2017 (UTC)[reply]
    - FWIW, the readability of this article is better than the amphetamine article based upon [12][13]. Seppi333 (Insert 2¢) 02:00, 20 December 2017 (UTC)[reply]
      - Fair enough. On re-read after all the changes you've made, I feel the article is quite a bit more readable. --Tom (LT) (talk) 22:18, 25 December 2017 (UTC)[reply]
"Several components of the signaling cascade that mediate the HMB-induced increase in human skeletal muscle protein synthesis have been identified " surely doesn't need 2 references
- The review lists the main component of the signaling cascade (mTORC1) and the secondary effects on GH/IGF-1 secretion in humans which was covered in that section (for context, GH and IGF-1 increase protein synthesis via mTORC1); the primary source lists all of the known downstream components in the signaling cascade (mTORC1, p70S6 kinase, 4EBP1) which HMB acts through. Seppi333 (Insert 2¢) 21:45, 13 December 2017 (UTC)[reply]
  - I won't push this particular point, but if they could be included where those respective products are listed I think it would reduce the burden of unnecessary references.To support the statement "several components... have been identified" really only needs a single source - the fact that several components have been identified by some person or group is not controversial --Tom (LT) (talk) 23:27, 14 December 2017 (UTC) for later reference[reply]
"Supplementation with HMB for one month in rats has also been shown to increase growth hormone and insulin-like growth factor 1 (IGF-1) signaling through their associated receptors in certain non-muscle tissues" if this is to do with non-muscles, then suggest move to the last paragraph
- GH and IGF-1 are hormones, so they circulate in blood plasma to all tissues. I think the ref was discussing non-muscle tissues in that specific context, however I added a 2nd statement from a new clinical review of human research on GH and IGF-1 secretion in response to resistance exercise in humans after that sentence. That 2nd sentence does pertain to GH/IGF-1 signaling in skeletal muscle, so, for contextual relevance, I've deleted "non-muscle" from the first sentence; it now says "... in certain tissues". (edited in this diff) Seppi333 (Insert 2¢) 21:45, 13 December 2017 (UTC)[reply]
  - Thanks. I still see this sentence as confusing. The paragraph opens with "Several components of the signaling cascade that mediate the HMB-induced increase in human skeletal muscle protein synthesis " so I am mentally expecting a paragraph about HMB and skeletal muscle, yet they we have a statement about use in other tissues. I think this should be moved to one of the other paragraphs. --Tom (LT) (talk) 23:27, 14 December 2017 (UTC)[reply]
    - GH and IGF-1 trigger protein synthesis through mTORC1 phosphorylation upon binding to their respective tyrosine receptor kinases; that's the reason I included the original sentence in that paragraph. Those two statements don't really have any relevance to the topics discussed in the last 2 paragraphs in that section (i.e., the paragraphs about intramuscular cholesterol and myosatellite cell proliferation/differentiation/fusion), but it is somewhat relevant to the muscle protein breakdown paragraph. I've further revised the wording so that the discussion about the effect on GH/IGF-1 in rats is easier to understand, more general, and more relevant to the discussion about the effect on those substances in humans (diff).Seppi333 (Insert 2¢) 08:40, 16 December 2017 (UTC)[reply]
      - Thanks, that makes a lot more sense. --Tom (LT) (talk) 23:20, 17 December 2017 (UTC)[reply]
Image two - (1) doesn't specificially mention HMB; (2) silly question, but couldn't find it answered in article. IS HMB a protein?
- Image 2 was included to illustrate the MPS response to exercise. It was included to give the reader an idea how much the baseline MPS is in response to exercise; the futher increase in response to HMB supplementation is listed in that section. If you think it should be removed, I'm ok with taking it out. Seppi333 (Insert 2¢) 20:22, 4 December 2017 (UTC)[reply]
- HMB is not a protein since it's not an amino acid complex; its chemical classification is covered in the chemistry section: "β-Hydroxy β-methylbutyric acid is a monocarboxylic β-hydroxy acid". Seppi333 (Insert 2¢) 20:22, 4 December 2017 (UTC)[reply]
  - Thanks for your thoughtful reply. I think that as HMB isn't a protein and this relates to MPS in response to protein ingestion, this is one step too far away from the primary topic of the article. I think we should remove it. --Tom (LT) (talk) 22:04, 12 December 2017 (UTC)[reply]
    - I've removed the 2nd image in that section (see this diff). Seppi333 (Insert 2¢) 22:52, 12 December 2017 (UTC)[reply]
"Based upon animal studies" -> could trim citations? (currently 4)
- I was able to cut two which made slightly different claims from the 2 that I didn't remove, but weren't necessary to fully support the sentence (see this diff). Seppi333 (Insert 2¢) 21:45, 13 December 2017 (UTC)[reply]

"may also facilitate the stabilization of " -> "may help stabilize" Done
"It is not clear if long-term supplementation with HMB in humans produces a similar increase in growth hormone and IGF-1 " if we are comparing against rats this is difficult to interpret, because the rats were given it for a 1 month but humans were taking it long-erm
- Re - the above bullet: since I added the material about the effect on GH/IGF-1 in humans based upon 1 small clinical trial that was included in a systematic review, I left that part in simply because it provides corroborating support from animal research for the statement in humans. Seppi333 (Insert 2¢) 21:45, 13 December 2017 (UTC)[reply]
  - Thanks. --Tom (LT) (talk) 23:27, 14 December 2017 (UTC)[reply]
"Similar to L-leucine" (1) suggest reinclude ", of which HMB is a product"; (2) I do not think you need to include the note, and if you do I suggest remove "in one study" as that would be a primary source.
1. I rephrased this as "Similar to HMB's metabolic precursor, L-leucine, ..." because stating that "HMB is a (metabolic) product of X" would really only make sense if that X was an enzyme, which has a substrate (e.g., leucine) and a product (e.g., HMB). I hope that wording is ok with you (edited in this diff). Seppi333 (Insert 2¢) 21:45, 13 December 2017 (UTC)[reply]
  - Thanks, much better. --Tom (LT) (talk) 23:27, 14 December 2017 (UTC)[reply]
2. The "in one study" clause in that sentence provides context for the statement, so I think removing it would make the context ambiguous. If you feel strongly about removing it, I will, but I don't think it would be helpful. In any event, since the sentences in all of the notes in the pharmacology section only discuss molecular biology, pharmacodynamic mechanisms, or pharmacokinetics without making any medical claims (at least not clinically relevant ones, depending upon how broadly the phrase "medical claims" is interpreted), the primary sources for those statements only really needs to satisfy the no OR restriction in WP:SCIRS#Respect primary sources and the other WP:SCIRS requirements (e.g., independent, up-to-date, peer-reviewed journal sources). Sourcing for similar content in articles on proteins, amino acids, and other biomolecules is typically governed by SCIRS because most endogenously synthesized compounds don't have medical uses. Seppi333 (Insert 2¢) 21:45, 13 December 2017 (UTC)[reply]
  1. I think the note should be removed, for the following reasons: I do not think it adds particularly to the paragraph or article; it relies on a single source, which makes it unreliable; it distracts from the flow of information; and I do not think it relates strongly enough to the sentence or paragraph to which it is attached to be included. --Tom (LT) (talk) 23:27, 14 December 2017 (UTC)[reply]
    The reliance on a single source is a valid issue, but I was actually planning on slightly expanding the note with coverage of a recently published primary source which examined the same parameters as the study which is cited in that note, but used HMB-Ca instead of HMB-FA. It found that the same effects occur with both HMB dosage forms and compared its results with the earlier primary source which is cited in the note. The purpose of the note is to specify an effect size for the increase in skeletal muscle protein synthesis (MPS) by HMB (i.e., it answers the question "how large is this increase?") in living humans; the entire paragraph in which the note is located only discusses how HMB affects MPS, so I don't understand why you think it has little relevance. Seppi333 (Insert 2¢) 21:11, 17 December 2017 (UTC)[reply]
    OK, I won't push this point. Can we move the note to the end of the sentence to improve readability? I will add a "" so that some of my ongoing concerns are noted in case somebody else mentions them in the FA. --Tom (LT) (talk) 23:20, 17 December 2017 (UTC)[reply]
    Done: Good idea – that's more consistent with the placement of the other notes in this section (diff). Seppi333 (Insert 2¢) 05:46, 18 December 2017 (UTC)[reply]

Chemistry

β-Hydroxy β-methylbutyric acid – the conjugate acid
Chemical formula: C
₅H
₁₀O
₃ (PubChem entry)

β-Hydroxy β-methylbutyrate – the conjugate base
Chemical formula: C
₅H
₉O⁻
₃ (PubChem entry)

Addressed

"A variety of synthetic routes " - >"HMB has been created in a number of ways" (this applies to the image caption too)
- Since MOS:MED#Drugs, treatments, and devices/MOS:PHARM#Sections specify that "Synthesis" be used as the title of this section, it seems a bit odd to replace the word "synthesis" in the text and leave it in the section title (NB: the content/sub-sections within the chemistry section were loosely based upon MOS:CHEM/Chemicals). Also, "synthetic routes" is wikilinked in this sentence (that's a link to a redirect to chemical synthesis) and I think the topic of the target page would be somewhat ambiguous if I put a piped-link to that article on the phrase created in a number of ways. Seppi333 (Insert 2¢) 07:56, 18 December 2017 (UTC)[reply]
  - Happy to leave this given MOS#MED, but I do think this article could be made more readable. This would help its content be communicated to a greater audience --Tom (LT) (talk) 01:29, 19 December 2017 (UTC)[reply]
The first reported chemical syntheses -> "The first creation chemically..."
- See the response to the preceding bullet. Seppi333 (Insert 2¢) 07:56, 18 December 2017 (UTC)[reply]

The comment below pertains to the discussion at FAC

"β-hydroxy β-methylbutyric acid" -> Mentioned lots of times here. Isn't this HMB? It would be best if, after the first mention in the lead, every other reference in the body uses HMB. I mention this only because in the second paragraph you do use that acronym and it's confusing because it implies they might be two different things
- In this particular section (Chemistry), using the full term for the conjugate acid (β-hydroxy β-methylbutyric acid) and conjugate base (β-hydroxy β-methylbutyrate) when discussing the properties of one or comparing the two is necessary because they're two distinct compounds (see the images to the right and their chemical formulas - the base has one less hydrogen atom than the acid and a negative charge on one oxygen atom). I believe (NB: Boghog wrote the entire subsection on synthesis; @Boghog: if you can comment on this, that'd be helpful) that specifying that the product is the acid matters for the synthesis subsection since a particular synthesis method might never yield the conjugate base. Nonetheless, since the entire chemical synthesis subsection is discussing the conjugate acid, I just left the first mention of HMB as the expanded term for the acid and converted all other instances to "HMB" in that subsection (diff). Seppi333 (Insert 2¢) 07:56, 18 December 2017 (UTC)[reply]
  - All rightly. --Tom (LT) (talk) 01:29, 19 December 2017 (UTC)[reply]
Why have you used the initial acronym (which does not state "free acid form" when all the other sections use the full form of the word? I think acronyms in general tend to make things less readable
- Fixed (assuming that you were referring to this) Seppi333 (Insert 2¢) 22:50, 12 December 2017 (UTC)[reply]
You surely do not need more than one citation for:
- "with the chemical formula C5H10O3" the chemical formula
  - The phrase you quoted requires only 1 reference, but 2 references are required to cite the entire sentence; if I were to cite it piece-wise, it would read: β-Hydroxy β-methylbutyric acid is a monocarboxylic^[1] β-hydroxy acid^[1] and natural product^[2] with the chemical formula C₅H₁₀O₃.^[1] – Seppi333 (Insert 2¢) 21:09, 11 December 2017 (UTC)[reply]
- "transparent, colorless to light yellow liquid which is soluble in water"
  - This phrase requires 3 references: transparent,^[3] colorless to light yellow liquid^[4] which is soluble in water.^[5] – Seppi333 (Insert 2¢) 21:09, 11 December 2017 (UTC)[reply]
    - Agree - you make a good point. --Tom (LT) (talk) 22:09, 12 December 2017 (UTC)[reply]
Suggest remove this unnecessary tidbit "(NaOCl, more commonly known as bleach)" and "(CO)" as the paragraph is already complicated enough
- Done: diff. Seppi333 (Insert 2¢) 07:56, 18 December 2017 (UTC)[reply]
The whole 'chemical structure' paragraph. Why do you need two references per line for things such as what is the conjugate acid and what is the conjugate base?
- One refs state the acid is the conjugate acid of the base, whereas the other ref states that the base is the conjugate base of the acid; hence, both refs are necessary to fully support the assertions in that sentence. Seppi333 (Insert 2¢) 21:17, 11 December 2017 (UTC)[reply]
"Synthesis" - am in favour putting on my simplification hat of renaming to "Creation" but acknowledge this may not be totally desired
- "Synthesis" is the correct title of this section according to MOS:MED#Drugs, treatments, and devices/MOS:PHARM#Sections. Seppi333 (Insert 2¢) 21:17, 11 December 2017 (UTC)[reply]
Great images by the way
- Thanks. Credit goes to User:Boghog for those. Seppi333 (Insert 2¢) 21:17, 11 December 2017 (UTC)[reply]
Suggest move the refractive index formula into a note, I am not sure how this adds to the text
- I don't think it's useful information to most readers, but Nergaal demanded that the chemistry section be expanded at [14], so Boghog added it to include more information about its chemical properties. I'm not sure Nergaal would be happy with that being placed in a note at the next FAC if he chooses to comment again. Seppi333 (Insert 2¢) 21:17, 11 December 2017 (UTC)[reply]
  - OK. Well I will note that I don't think it's useful, is unnecessary jargon and excessively technical, and also we are not a manual (WP:NOT) and leave it at that - this can be discussed more in FA if other editors comment on it. --Tom (LT) (talk) 22:09, 12 December 2017 (UTC)[reply]

Detection in body fluids

"Endogenously synthesized HMB has been detected and quantified in several human biofluids " -> HMB created by the body has been found and measured in several human fluids" – Done
"e average molar concentration of HMB has been quantified at 4.0 micromolar (μM) -> "The average concentration has been measured at 4.0 μm (micromolar)"
- "4.0 micromolar (μM)" is the format specified by MOS:UNITNAMES for introducing units that readers are expected to not know. (Units unfamiliar to general readers should be presented as a name–symbol pair on first use, linking the unit name (Energies were originally 2.3 megaelectronvolts (MeV), but were eventually 6 MeV).)
  - OK, fair enough. --Tom (LT) (talk) 22:09, 12 December 2017 (UTC)[reply]
Suggest change all "quantified" -> "measured" for readability – Done
Suggest remove all the acronyms, as they are all used only once (including NMR, LC-MS, GC-MS, and even potentially CSF)
- Done: removed the first 3. CSF is listed in the table, so I think that's better to leave in (diff). Seppi333 (Insert 2¢) 05:51, 18 December 2017 (UTC)[reply]

References

^ ^a ^b ^c "3-hydroxyisovaleric acid". Chemical Entities of Biological Interest. European Bioinformatics Institute. 23 October 2015. Retrieved 20 August 2016.
^ "3-Hydroxyisovaleric acid". HMDB Version 3.6. Human Metabolome Database. 11 February 2016. Retrieved 25 May 2016.
^ WO application 2015094925, White TO, "Stable liquid filled hard capsule comprising beta-hydroxy-beta-methylbutyric acid", published 25 June 2015, assigned to Capsugel Belgium Nv
^ "Beta-Hydroxyisovaleric acid". ChemicalBook. Retrieved 20 August 2016.
^ 3-OH-isovaleric acid. Royal Society of Chemistry. Retrieved 10 August 2016. Experimental Boiling Point: ... 128 °C / 7 mm ...
Experimental solubility:
Soluble in water {{cite encyclopedia}}: |work= ignored (help)

History

No comments, easy to understand and fairly interesting

In general

Excellent article you have clearly put a lot of effort into
Too many references - (1) should be trimmed if at all possible, especially when single facts have multiple references; (2) lead seems to have more references than the body for some things, this should surely be reversed
- Thank you, I can see you've tried to trim the references and appreciate this. --Tom (LT) (talk) 22:26, 25 December 2017 (UTC)[reply]
Some language used in the article is quite technical and could be simplified to enhance readability
- Suggest you quickly run through the article and standardise all spellings of HMB to the acronym HMB and HMB-FA, as currently they alternate making this quite difficult to read at times
  - The only place in the article (as of today) where the expanded/full term was used, but the acronym could be used instead, was in the history section; I've updated that section accordingly (diff). The use of HMB-Ca and HMB-FA and the remaining uses of the expanded/full terms are in places where using the acronym "HMB" would not be appropriate since the text is referring specifically to one commercial formulation, the conjugate acid, or the conjugate base in those contexts. "HMB" refers to all of those collectively. Seppi333 (Insert 2¢) 07:18, 20 December 2017 (UTC)[reply]
    - Edit: after reconsideration, I decided to standardize HMB-Ca and HMB-FA to HMB in the side effects section as well since the difference in the dose of HMB between HMB-Ca and HMB-FA is pretty small (diff). Almost all clinical studies used 3 g of either formulation anyway. Seppi333 (Insert 2¢) 23:34, 21 December 2017 (UTC)[reply]
      - Thanks. The article's readability has improved (in my eyes at least) throughout the review.
Images are excellent
Won't delve in to the sources used that much other than to say for posterity's sake that they will need a closer look in FA several of them are primary sources and small scale studies

I hope this review helps. Will start working through your replies in the next day or so. Cheers --Tom (LT) (talk) 22:50, 8 December 2017 (UTC)[reply]

@Tom (LT): I combed through the references and compiled the list below that includes every primary source cited in the article which has a PMID number (the handful of other primary sources cite statements in chemistry, history, etc., so they're all covered by WP:RS).

Primary sources with a PMID # that were cited in this article – the sections in the body where these are cited are listed in parentheses:

~~PMID 18293016 – included in medical section, but doesn't support a medical claim - only comments on the adequancy of the study~~ Removed

PMID 24495238 – supports statements about concentrations in bovine milk and food fortification with HMB (~~Available forms,~~ Detection in body fluids)
PMID 26271627 – supports statements about presence in human milk and its concentration range (Detection in body fluids)
PMID 26373270 – support its commercial availability and statements about its pharmacokinetics (Available uses, Pharmacokinetics)
PMID 21918059 – support statements about its metabolic pathway (Biosynthesis)
PMID 19211028 – supports which protein kinases, myogenic factors, or transcription factors mediate the effects that were identified in reviews of in vitro research, but which glossed over the details (Pharmacodynamics)
PMID 27499494 – supports only the following sentence in a reference note: Since all T cells are CD3+, a measure of CD3+ cells is used as a general estimate of total T cells. (Special:permalink/814463242#cite_note-39)
PMID 23551944 – supports statements about pharmacodynamics & concentration in blood plasma following oral ingestion (Pharmacodynamics, Detection in body fluids)
- PMID 29097038 – not currently cited, but was planning to add this to the article to support statements in pharmacodynamics and detection in body fluid; this study is analogous to the one in the bullet immediately above.

Seppi333 (Insert 2¢) 00:02, 9 December 2017 (UTC)[reply]

COMMENT: Under the rubric of "less is more," I find it unnecessary and annoying that so many of the references include extended quotation of material from the abstracts or articles. Some exceeding 150 words and containing mention of references in the cited article. If the information is essential to the article it belongs in the article. If not, it does not belong anywhere. I've rarely seen reference bloat of this nature, and this is a particularly egregious example. David notMD (talk) 15:45, 12 December 2017 (UTC)[reply]

@David notMD: The extended quotes are there so that I don't need to constantly sift back through the refs during FAC when people challenge whether or not material is supported by a reference, which occurs at every FAC. I intend to censor all of the ref quotes to at most 5 sentences after a WP:V check is finished. I'm not going to censor them now though. Seppi333 (Insert 2¢) 17:57, 12 December 2017 (UTC)[reply]

Appreciate the explanation. Whenever I am trying to uplift an article to GA status, my workspace is strewn with printouts of abstracts and pages from PDFs of articles. I've yet to attempt a FA. NOTE: I do agree with the too-many-refs comment from the GA reviewer, but again, some of that probably in anticipation of FA submittal. David notMD (talk) 18:08, 12 December 2017 (UTC)[reply]

Conclusion

Thanks for your patience, Seppi333. This is a great article that you've put a lot of effort into. With your many changes I feel the article has improved to meet GA criteria. I have one or two concerns that I feel we are at loggerheads here with and will pop on the article's talk page, but nothing that would mean this article shouldn't become a GA. Thanks for your responsiveness; Merry Christmas! --Tom (LT) (talk) 22:26, 25 December 2017 (UTC)[reply]

Thanks again for doing the GA review of this article Tom! I really appreciate all the time and effort you put into reviewing it; I think it was very constructive/helpful.

Seppi333 (Insert 2¢) 22:30, 25 December 2017 (UTC)[reply]

Small additional concerns

Some small additional concerns. I don't think these are enough to prevent a successful GA nomination, and they have been discussed with Seppi333 during the nomination and we have reached a loggerheads. I note these with a view to a (1) FA nomination and (2) MEDRS compliance:

I still think some work could be done paring down references
I think information relating to the lack of effects of overdose should be included in text
I am concerned that primary sources are used to make medical claims, which is not something recommended by our WP:MEDRS
- "One clinical trial with Juven for AIDS also demonstrated improvements in immune status, as measured by a reduced HIV viral load relative to controls and higher CD3+ and CD8+ cell counts"
- "The efficacy of Juven for the treatment of cancer cachexia was also examined in a phase 3 clinical trial which found a strong trend (i.e., p=.08) for an improvement in lean body mass relative to controls"
I do not think that the article needs so many notes (I think most could be removed without damaging the article's integrity)

It would be useful if a third editor could comment on these; Seppi333 makes some good points and it may be useful if a third or fourth editor could offer their opinion on the above. Have a lovely festive season, --Tom (LT) (talk) 22:53, 25 December 2017 (UTC)[reply]

@Tom (LT): Re: "The efficacy of Juven for the treatment of cancer cachexia was also examined in a phase 3 clinical trial which found a strong trend (i.e., p=.08) for an improvement in lean body mass relative to controls"

Given that this is a primary study showing a non-statistically significant trend, and the cited systematic review essentially says it's useless, this should probably be removed. PriceDL (talk) 00:11, 26 December 2017 (UTC)[reply]

Generally speaking, I am never been in favor of removing references because there are too many and need to be pared down. Sure, some refs may not be MEDRS and removed, but medical topics need to be rich with references and if ten superscripted numerals aren't appropriate in the 'reader's' of the article, retain the references in the wiki-markup view. These references can then be 'reactivated' as other references become outdated. Perhaps I am sensitive to the referencing issues brought up, but there is no need to remove them just because there are too many. Best Regards, Barbara (WVS) ✐ ✉ 15:02, 2 March 2018 (UTC)[reply]

Citing a new chemistry claim

β-Hydroxy β-methylbutyric acid is a member of the carboxylic acid family of organic compounds and like them, it is a weak acid.

@EdChem: Would you happen to know of a source that can be used to cite this statement? Seppi333 (Insert 2¢) 09:56, 17 April 2018 (UTC)[reply]

Is a citation needed? The diagram of the molecule in the infobox shows a carboxyl group. Care to differ or discuss with me? The N^th User 02:12, 1 June 2018 (UTC)[reply]

The only claim in that sentence that really needs a citation is the assertion that carboxylic acids are weak acids. "β-Hydroxy β-methylbutyric acid is a monocarboxylic β-hydroxy acid" is cited in the previous paragraph. Seppi333 (Insert 2¢) 21:18, 1 June 2018 (UTC)[reply]

The weak acid article supports the general pattern that carboxylic acids are weak, and the enumeration of the strong acid general types and specific examples does not include any. But surprisingly, neither acid strength (target of the weak acid redirect) nor carboxylic acid actually directly cite this specific pattern of this functional group! So "like them" is still not strictly WP:V. DMacks (talk) 05:07, 7 June 2018 (UTC)[reply]

@DMacks: So, do you think this statement should be rephrased to something along the lines of the following sentence?

"β-Hydroxy β-methylbutyric acid is a weak acid and a member of the carboxylic acid family of organic compounds."

If it's rephrased in that manner, the only thing that needs to be cited is the assertion that HMB is a weak acid. I might be able to find a citation for that assertion own my own. Seppi333 (Insert 2¢) 01:22, 10 June 2018 (UTC)[reply]

"Weak acid" is a mechanical definition based on the pKa. The pKa value is given and cited in the previous section. So maybe the "weak acid" detail should be moved to there rather than where it is now if we are stating a bare fact rather than making a "chemical structure" explanation? So in the second-level "Chemistry" section:

β-hydroxy β-methylbutyric acid is a weak acid, having a pK_a 4.4. Its refractive index...

and then later in the "Chemical structure" section:

β-hydroxy β-methylbutyric acid is a member of the carboxylic acid family of organic compounds. It is a structural analog...

DMacks (talk) 02:39, 10 June 2018 (UTC)[reply]

That sounds reasonable. I'll make the change. Seppi333 (Insert 2¢) 19:41, 11 June 2018 (UTC)[reply]

@Seppi333: I don't really think any citation was needed as the fact that it is a carboxylic acid and a weak acid is utterly uncontroversial and unlikely to be challenged by anyone. Nevertheless, I also agree with DMacks that the pK_a value confirms that it is a weak acid, and the form of words proposed and implemented from your discussion is accurate. Sorry for the delay in responding. EdChem (talk) 12:04, 20 July 2018 (UTC)[reply]

No problem. It probably wouldn't be challenged, but article content in FAs needs to be verifiable. Seppi333 (Insert 2¢) 02:04, 21 July 2018 (UTC)[reply]

Conjugate base

There appears to be disagreement on whether Beta-Hydroxy beta-methylbutyrate should be described like an alternate name of Beta-Hydroxy beta-methylbutyric acid in the lead. While the two are closely related (They're each other's conjugate acid/base.), I think that the article needs to recognize that they're not exactly the same molecule. Care to differ or discuss with me? The N^th User 02:10, 1 June 2018 (UTC)[reply]

The current version is fine with me. Seppi333 (Insert 2¢) 21:18, 1 June 2018 (UTC)[reply]

I still think that saying that the two conjugates are the same as each other is a simple factual error. Besides prominence of the subject, the case would be exactly the same if Wikipedia said that water was the same as hydronium or hydroxide. Care to differ or discuss with me? The N^th User 02:57, 2 June 2018 (UTC)[reply]

@The Nth User: I completely understand what you're saying. Strictly from a chemistry viewpoint, the two compounds are different in many ways. From a pharmacological/molecular biological, medical, and even biochemical viewpoint though, the two are entirely interchangeable since their pharmacological/cellular properties/effects (e.g., the signaling cascades that they trigger in humans, the resulting effects on muscle protein synthesis/breakdown in humans in vivo, and their presumed biomolecular targets), clinical properties/effects (e.g., effects on lean body mass, recovery time, muscle strength/power, etc. in humans in vivo), and metabolic properties/effects (i.e., biosynthesis and metabolism, due to the fact that these compounds are readily converted to one another in the body, dependent upon the pH of the biofluid compartment where they're distributed) are equivalent; in other words, for the purpose of describing each of those aspects, the acid and base are interchangeable and simultaneous reference to both via the abbreviation "HMB" is desirable/merited.

I've done my best to balance the fact that they're not equivalent from a chemical viewpoint but are from most other viewpoints by including coverage of both chemical structure diagrams in the drugbox (i.e., the two are very prominently displayed in the drugbox, which makes it abundantly clear that there's a structural difference between them in one of the acid's two hydroxyl groups and a difference in their molecular formulas). I also stopped using the catch-all abbreviation "HMB" in the Beta-Hydroxy beta-methylbutyric acid#Chemistry section and instead used the expanded names of the conjugate acid and base to differentially cover their chemical properties. That's literally the only section of the article where doing this was actually necessary because the vast majority of assertions elsewhere in the article apply simultaneously to both the acid and the base. If you have a better idea about how to go about doing this, let me know. I'm open to modifying the coverage of the distinction in the lead provided that it doesn't create ambiguity about the equivalence of the pharmacological, medical, and biochemical properties. Seppi333 (Insert 2¢) 01:44, 10 June 2018 (UTC)[reply]

Actually, what I said above wasn't completely accurate; differential coverage of HMB-Ca and HMB-FA was necessary in a few sections of the article since the calcium moiety in HMB-Ca modifies the pharmacokinetic properties (i.e., uptake/distribution) and slightly modifies the magnitude of the clinical and cellular/pharmacodynamic effects of the compound relative to HMB-FA (i.e., pure β-hydroxy β-methylbutyric acid). Even so, there are many statements in the article that cover aspects of those topics where differential coverage of HMB-Ca and HMB-FA was/is not necessary. Seppi333 (Insert 2¢) 01:48, 10 June 2018 (UTC)[reply]

@Seppi333: The article now is fine. I just wanted a clarification that they were two separate chemicals at the top. But if anything good came out of this, I got the idea for conjugate acid and base parameters to be added to Template:Chembox. Care to differ or discuss with me? The N^th User 18:43, 16 June 2018 (UTC)[reply]

Long and repetitive introduction

Most of the content in the introduction is repeated literally word-for-word in the article body. In my revisions I removed all the duplicate info], repeated word for word in the body. I read other bioactive chemical pages and they don’t have the extreme repetitiveness of this article. The intro almost reads as an advertisement for HMB, let your customers read the article first. Anyway, I saw no reason given for undoing my copyedits, why were they removed? Dogshu (talk) 13:04, 29 August 2018 (UTC)[reply]

@Dogshu: sorry for the delayed reply. The lead/intro section of an article is supposed to summarize the body of the article. Article leads should not contain any information which is not stated in the body, with exception for very basic facts about the article topic (e.g., synonyms, topical scope, etc.). Consequently, a well-written article lead should be fairly redundant with the body and adhere to WP:SUMMARYSTYLE. Seppi333 (Insert 2¢) 23:05, 30 August 2018 (UTC)[reply]

@Seppi333:Yes it should be redundant. However entire sections of the intro are repeated verbatim in the body. My revision preserved the references to the content without repeating whole sections verbatim. I know I’m a newb though, and accept your decision, unless anyone else dissents. I am curious however if those that want all the information up front in the intro, making it sound like a miracle drug, have ties to the food supplement industry and are thus biased. Dogshu (talk) 02:18, 31 August 2018 (UTC)[reply]

@Dogshu: Hmm. Well, the sentences in the lead don't necessarily have to differ from the body, but I suppose "good writing" entails at least a little variation when assertions are restated. This reminds me of a general question that I asked about redundant article content when I was a new editor (User talk:Seppi333/Archive 1#Content Redundancy Q), although IIRC the issue that led to me asking that had more to do with restated assertions within different sections of the article's body. Anyway, when I wrote this article, I basically just either summarized several paragraphs of text from the body in 1-2 sentences or copy/pasted the key points and contextual facts from every section of the body. That said, if you want to superficially rephrase the duplicate sentences in the lead section so that they're not verbatim duplicates of the text in the article's body, that would be completely fine with me.

As for the efficacy of this drug, this article's lead currently states a direction of an effect without quantifying how large the effects are (AKA the magnitude or effect size); more clinical research needs to be conducted in resistance-trained individuals (i.e., people who perform strength/resistance training on a regular basis), endurance athletes, and untrained athletes before a meta-analysis can be performed to determine the effect size of HMB supplementation for each population group. Based upon current evidence, the effect of HMB on muscle mass tends to be smaller in individuals who perform strength training on a regular basis relative to untrained groups. That said, the effect size in older adults has been estimated by a meta-analysis of clinical trials and is included in a note within the body of this article (see beta-Hydroxy beta-methylbutyric acid#cite note-36), but this content isn't covered in the article's lead section; based upon the estimated standard mean difference and the weighted average duration listed in that note, daily HMB supplementation in older adults appears to produce an annual increase in skeletal muscle mass by ~1.5 pounds on average. That's a rather notable fact since sedentary older adults lose muscle mass on an annual basis, and some lose much more. Seppi333 (Insert 2¢) 00:44, 2 September 2018 (UTC)[reply]

Addendum: I included the note I mentioned above at the end of the corresponding sentence in the lead in this edit. Seppi333 (Insert 2¢) 00:48, 2 September 2018 (UTC)[reply]

Updates - recent (post-FA) reviews and meta-analyses

From this search:

Meta-analyses from 2018

PMID 29249685; meta-analysis: performance-enhancement literature High Priority Added
PMID 29676656; meta-analysis + systematic review: healthy adults - presumably mostly athletes (effect on exercise-induced muscle damage) High Priority Added

Systematic reviews from 2018

PMID 29300431 - systematic review: elderly/clinical High Priority
PMID 29941852 - systematic review: clinical population - post-surgical recovery High Priority

Other reviews from 2017–2018

PMID 28683706 - review by Cruz-Jentoft that I missed earlier High Priority

Add these when time permits:

PMID 29345167 - review: athletes
PMID 29804584 - (narrative?) review: elderly ("aging neuromuscular junction")
PMID 30237683 - sports pharmacology review
PMID 29182451 - review: athletes
PMID 29045254 - review

Seppi333 (Insert 2¢) 21:36, 23 October 2018 (UTC)[reply]

Lead breaks on mobile phones in desktop view

This is what the beginning of the article looks like in desktop view on my Huawei P20 Pro: https://i.imgur.com/zyevlQK.jpg

Is it necessary to put the conjugate base in a {{nowrap}}? The full, acid name is not in a nowrap. Cheers, Manifestation (talk) 10:49, 26 February 2019 (UTC)[reply]

That's a good point. I support nowrap or other methods to keep each beta with its next word, but no need to keep separate words together. I changed it to allow breaking at the whitespace, as the acid itself is, as you note. DMacks (talk) 15:34, 26 February 2019 (UTC)[reply]

@DMacks: Great! It works. Thanks a lot, Manifestation (talk) 16:25, 27 February 2019 (UTC)[reply]

Myoplex

This article mentions the supplement Myoplex three times: once in the lead, once under "Use", and once under "History". However, the brand under which the formulation was distributed, EAS, has been discontinued as of June 2018 by its parent, Abbott Laboratories (see here and here). Therefore, I assume Myoplex is no longer being produced. Many shops still have it in stock, but I guess they will run out eventually. Cheers, Manifestation (talk) 17:09, 27 February 2019 (UTC)[reply]

Removed it Seppi333 (Insert 2¢) 20:27, 1 August 2023 (UTC)[reply]

Sources of HMB

There is little to no information about where companies are sourcing HMB for human consumption. Where is the compound coming from? Animals? Plants? Mining? 2603:6011:5840:77:E883:6958:855B:D2FC (talk) 14:51, 29 May 2023 (UTC)[reply]

There’s an entire section on chemical synthesis … Seppi333 (Insert 2¢) 20:27, 1 August 2023 (UTC)[reply]

Source update

There are scores of very recent secondary reviews in PubMed, and yet most of the sourcing in the Uses section of this article are dated. SandyGeorgia (Talk) 13:39, 1 August 2023 (UTC)[reply]

Where is supplements purged, under what brand name. 67.4.0.15 (talk) 19:30, 1 August 2023 (UTC)[reply]

Might update it in a year or two. Seems fine right now. Seppi333 (Insert 2¢) 20:14, 1 August 2023 (UTC)[reply]

[ISSN_position_stand_2013-1] Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". J. Int. Soc. Sports. Nutr. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064. PMID 23374455. The International Society of Sports Nutrition (ISSN) bases the following position stand on a critical analysis of the literature on the use of beta-hydroxy-beta-methylbutyrate (HMB) as a nutritional supplement. The ISSN has concluded the following. 1. HMB can be used to enhance recovery by attenuating exercise induced skeletal muscle damage in trained and untrained populations. 2. If consuming HMB, an athlete will benefit from consuming the supplement in close proximity to their workout. 3. HMB appears to be most effective when consumed for 2 weeks prior to an exercise bout. 4. Thirty-eight mg·kg·BM-1 daily of HMB has been demonstrated to enhance skeletal muscle hypertrophy, strength, and power in untrained and trained populations when the appropriate exercise prescription is utilized. 5. Currently, two forms of HMB have been used: Calcium HMB (HMB-Ca) and a free acid form of HMB (HMB-FA). HMB-FA may increase plasma absorption and retention of HMB to a greater extent than HMB-CA. However, research with HMB-FA is in its infancy, and there is not enough research to support whether one form is superior. 6. HMB has been demonstrated to increase LBM and functionality in elderly, sedentary populations. 7. HMB ingestion in conjunction with a structured exercise program may result in greater declines in fat mass (FM). 8. HMB's mechanisms of action include an inhibition and increase of proteolysis and protein synthesis, respectively. 9. Chronic consumption of HMB is safe in both young and old populations. ... HMB is naturally produced in animals and humans from the amino acid leucine [27]. The first step in production of HMB is the reversible transamination of leucine to α-keto-isocaproate (KIC) by the enzyme branched chain amino acid transferase [28] ... KIC is primarily metabolized into isovaleryl-CoA, with only approximately 5% of leucine being converted into HMB [28]. To put this into perspective, an individual would need to consume over 600 g of high quality protein to obtain the amount of leucine (60 grams) necessary to produce the typical 3 g daily dosage of HMB used in human studies [9]. Since consumption of this amount of protein is impractical, HMB is typically increased via dietary supplementation.

[Skeletal_muscle_homeostasis_2016_review-2] Brook MS, Wilkinson DJ, Phillips BE, Perez-Schindler J, Philp A, Smith K, Atherton PJ (January 2016). "Skeletal muscle homeostasis and plasticity in youth and ageing: impact of nutrition and exercise". Acta Physiol (Oxf). 216 (1): 15–41. doi:10.1111/apha.12532. PMC 4843955. PMID 26010896. The mechanisms regulating loss of skeletal muscle mass with age still remain unclear; however, with the shrinkage of any organ (other than necrosis), they must be due to chronic imbalances between protein synthesis (MPS) and protein breakdown (MPB), that is MPB > MPS. ... Therefore, in the post‐absorptive state, rates of MPB > MPS leading to a net negative protein balance and hence a loss of muscle protein. Crucially, this negative protein balance is transiently reversed (MPS > MPB) after food intake (contingent on sufficient high‐quality protein), such that net protein balance is neutral on a daily basis (MPS = MPB). The mechanisms underlying the anabolic effects of food intake involve both the stimulation of MPS (Rennie et al. 1982) and suppression of MPB (Wilkes et al. 2009). The potent increase in MPS is driven almost entirely by essential amino acids (EAAs) (Smith et al. 1992), with the branched chain AA (BCAA: leucine, isoleucine and valine), in particular leucine [and its metabolite(s), e.g. β‐hydroxy β‐methylbutyric acid (HMB) (Van Koevering & Nissen 1992)] being central to these effects (Wilkinson et al. 2013). ... Despite extensive investment in pharmaceutical interventions (Onder et al. 2009) and the discovery of a number of potential novel targeted pharmaconutrients [ursolic acid (UA), HMB, PA, etc. (Vukovich et al. 2001, Kunkel et al. 2011, Hoffman et al. 2012)], RE with appropriate supportive nutrition remains the current most effective and safe means by which to maintain or increase muscle mass in older adults (Ivey et al. 2000, Parise & Yarasheski 2000, Häkkinen et al. 2001, Kumar et al. 2012). ... More recent studies have shown that some nutritional supplements such as the leucine metabolite HMB, which is known to have potent affects on both MPS and MPB (Wilkinson et al. 2013), have potential to prevent or slow the decline in bed rest‐related muscle loss (Deutz et al. 2013), indicating the importance of nutritional strategies for assisting in combating the accelerated mass loss (Magne et al. 2013).

[Review_July_2010-3] Portal S, Eliakim A, Nemet D, Halevy O, Zadik Z (July 2010). "Effect of HMB supplementation on body composition, fitness, hormonal profile and muscle damage indices". J. Pediatr. Endocrinol. Metab. 23 (7): 641–50. doi:10.1515/jpem.2010.23.7.641. PMID 20857835. S2CID 2209268. There is a huge market for ergogenic supplements for athletes. However, only a few products have been proven to have ergogenic effects and to be effective at improving muscle strength and body composition. One such supplement is beta-hydroxy beta-methylbutyrate (HMB). ... Several studies have shown that combining exercise training with HMB supplementation leads to increased muscle mass and strength, and there is some anecdotal evidence of aerobic improvement. However, HMB supplementation has been found to be effective mainly for untrained individuals. While previous reviews have emphasized three main pathways for HMB's mode of action: 1) enhancement of sarcolemmal integrity via cytosolic cholesterol, 2) inhibition of protein degradation via proteasomes, and 3) increased protein synthesis via the mTOR pathway, more recent studies have suggested additional possible mechanisms for its physiological effects. These include decreased cell apoptosis and enhanced cell survival, increased proliferation, differentiation and fusion via the MAPK/ERK and PI3K/Akt pathways, and enhanced IGF-I transcription.

[Sarcopenia_November_2014_systematic_review-4] Cruz-Jentoft AJ, Landi F, Schneider SM, Zúñiga C, Arai H, Boirie Y, Chen LK, Fielding RA, Martin FC, Michel JP, Sieber C, Stout JR, Studenski SA, Vellas B, Woo J, Zamboni M, Cederholm T (November 2014). "Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS)". Age Ageing. 43 (6): 748–59. doi:10.1093/ageing/afu115. PMC 4204661. PMID 25241753. Essential amino acid (EAA) supplements, including ∼2.5 g of leucine, and β-hydroxy β-methylbutyric acid (HMB) supplements, show some effects in improving muscle mass and function parameters. Protein supplements have not shown consistent benefits on muscle mass and function. ... Supervised resistance exercise is recommended for individuals with sarcopenia. EAA (with leucine) and HMB may improve muscle outcomes. ...
HMB supplementation
The effect of HMB alone [32, 36] or HMB in combination with ARG and LYS [34] or resistance exercise training [39] on muscle parameters has been investigated in four high-quality (PEDro score: 8–10) studies of 8–24-week duration in community-dwelling older adults [34, 36, 39] or in healthy older adults on extended bed rest [32]. HMB prevented muscle mass loss in one of four studies and did not improve muscle mass in the other three [32]; improved muscle strength in one [34] (and possibly two) [36] of four studies and improved physical performance in one of four studies [34].
Overall, HMB showed some effects on muscle mass and function in these high-quality studies, but sample sizes were small.

[Systematic_review_December_2013-5] Molfino A, Gioia G, Rossi Fanelli F, Muscaritoli M (December 2013). "Beta-hydroxy-beta-methylbutyrate supplementation in health and disease: a systematic review of randomized trials". Amino Acids. 45 (6): 1273–1292. doi:10.1007/s00726-013-1592-z. PMID 24057808. Beta-hydroxy-beta-methylbutyrate (HMB), a metabolite of the branched-chain amino acid leucine, is extensively used by athletes and bodybuilders in order to increase strength, muscle mass and exercise performance. ... The indexed studies support that HMB is effective in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases. Most of the selected studies showed the effectiveness of HMB in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases. The usual dose of 3 g/day may be routinely recommended to maintain or improve muscle mass and function in health and disease. The safety profile of HMB is unequivocal. Further, well-designed clinical studies are needed to confirm effectiveness and mode of action of HMB, particularly in pathological conditions.

[Meta-analytic_systematic_review_September_2015-6] Wu H, Xia Y, Jiang J, Du H, Guo X, Liu X, Li C, Huang G, Niu K (September 2015). "Effect of beta-hydroxy-beta-methylbutyrate supplementation on muscle loss in older adults: a systematic review and meta-analysis". Arch. Gerontol. Geriatr. 61 (2): 168–175. doi:10.1016/j.archger.2015.06.020. PMID 26169182. RESULTS: A total of seven randomized controlled trials were included, in which 147 older adults received HMB intervention and 140 were assigned to control groups. The meta-analysis showed greater muscle mass gain in the intervention groups compared with the control groups (standard mean difference=0.352kg; 95% confidence interval: 0.11, 0.594; Z value=2.85; P=0.004). There were no significant fat mass changes between intervention and control groups (standard mean difference=-0.08kg; 95% confidence interval: -0.32, 0.159; Z value=0.66; P=0.511).
CONCLUSION: Beta-hydroxy-beta-methylbutyrate supplementation contributed to preservation of muscle mass in older adults. HMB supplementation may be useful in the prevention of muscle atrophy induced by bed rest or other factors. Further studies are needed to determine the precise effects of HMB on muscle strength and physical function in older adults.

[PEDs_in_sports_2015_review-7] Momaya A, Fawal M, Estes R (April 2015). "Performance-enhancing substances in sports: a review of the literature". Sports Med. 45 (4): 517–531. doi:10.1007/s40279-015-0308-9. PMID 25663250. S2CID 45124293.
3.6 Beta-Hydroxy-Beta-Methylbutyrate
HMB is a metabolite of the amino acid leucine and is a precursor to cholesterol. ... A 2013 NCAA survey study reported a 0.2 % rate of use among all student athletes [13]. However, it appears that HMB is increasingly being added to many training regimens [88]. ... There are several proposed mechanisms by which HMB acts. One of the primary mechanisms involves the up-regulation of the mechanistic target of rapamycin/ p70S6K signaling pathway, which promotes protein synthesis and muscle hypertrophy [89].
Other studies have focused on the anti-catabolic effects of HMB. Smith et al. [90] demonstrated that HMB preserved lean body mass and decreased proteolysis through the down-regulation of the increased expression of certain components of the ubiquitin–proteasome proteolytic pathway. Some studies have examined HMB and its effect on muscle by measuring markers of muscle breakdown. Wilson et al. [91] demonstrated that when non-resistance trained males received HMB pre-exercise, the rise of lactate dehydrogenase (LDH) levels reduced, and HMB tended to decrease soreness. Knitter et al. [92] showed a decrease in LDH and creatine phosphokinase (CPK), a byproduct of muscle breakdown, by HMB after a prolonged run. ... Despite differences in these studies, it does appear that HMB overall enhances muscular hypertrophy, strength, and power. In fact, the International Society for Sports Nutrition, in a position statement, writes that HMB can be used to enhance recovery by reducing skeletal muscle damage after exercise in athletically trained and untrained people. The utility of HMB does seem to be affected by timing of intake prior to workouts and dosage [97]. Further, chronic consumption of HMB appears safe [97]. ... Currently, HMB is available as an over-the-counter supplement. The drug is not tested for nor banned by any sporting organization.

[Molecular_Aspects_of_Medicine_2016_review-8] Brioche T, Pagano AF, Py G, Chopard A (April 2016). "Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention" (PDF). Mol. Aspects Med. 50: 56–87. doi:10.1016/j.mam.2016.04.006. PMID 27106402. S2CID 29717535. In conclusion, HMB treatment clearly appears to be a safe potent strategy against sarcopenia, and more generally against muscle wasting, because HMB improves muscle mass, muscle strength, and physical performance. It seems that HMB is able to act on three of the four major mechanisms involved in muscle deconditioning (protein turnover, apoptosis, and the regenerative process), whereas it is hypothesized to strongly affect the fourth (mitochondrial dynamics and functions). Moreover, HMB is cheap (~30–50 US dollars per month at 3 g per day) and may prevent osteopenia (Bruckbauer and Zemel, 2013; Tatara, 2009; Tatara et al., 2007, 2008, 2012) and decrease cardiovascular risks (Nissen et al., 2000). For all these reasons, HMB should be routinely used in muscle-wasting conditions especially in aged people.

[HMB_athletic_performance-related_effects_2011_review-9] Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (April 2011). "HMB supplementation: clinical and athletic performance-related effects and mechanisms of action". Amino Acids. 40 (4): 1015–1025. doi:10.1007/s00726-010-0678-0. PMID 20607321. S2CID 11120110.

[HMB_for_cancer_cachexia_2013_review-10] Kim JS, Khamoui AV, Jo E, Park BS, Lee WJ (October 2013). "β-Hydroxy-β-methylbutyrate as a countermeasure for cancer cachexia: a cellular and molecular rationale". Anticancer Agents Med. Chem. 13 (8): 1188–1196. doi:10.2174/18715206113139990321. PMID 23919746.

[Effects_of_amino_acid_derivatives_2015_review-11] Luckose F, Pandey MC, Radhakrishna K (2015). "Effects of amino acid derivatives on physical, mental, and physiological activities". Crit. Rev. Food Sci. Nutr. 55 (13): 1793–1807. doi:10.1080/10408398.2012.708368. PMID 24279396. S2CID 22657268. Creatine, carnitine, HMB, and taurine are reported to delay the onset of fatigue, improve exercise performance, and body strength. HMB helps in increasing fat-free mass and reduce exercise induced muscle injury. ... [Need full text for more detail]

[Muscle_atrophy-related_signal_transduction_review-12] Dutt V, Gupta S, Dabur R, Injeti E, Mittal A (September 2015). "Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action". Pharmacol. Res. 99: 86–100. doi:10.1016/j.phrs.2015.05.010. PMID 26048279.

[HMB_clinical_evidence_2016_review-13] Landi F, Calvani R, Tosato M, Martone AM, Ortolani E, Savera G, D'Angelo E, Sisto A, Marzetti E (May 2016). "Protein Intake and Muscle Health in Old Age: From Biological Plausibility to Clinical Evidence". Nutrients. 8 (5): 295. doi:10.3390/nu8050295. PMC 4882708. PMID 27187465. Given the role of leucine as the master dietary regulator of muscle protein turnover, the ingestion of protein sources enriched with this essential amino acid, or its metabolite β-hydroxy β-methylbutyrate, is thought to offer the greatest benefit in terms of preservation of muscle mass and function in old age. ... Recently, it has been demonstrated that β-hydroxy β-methylbutyrate (HMB)—an amino acid metabolite of leucine—is able to stimulate protein synthesis and improve muscle strength and body composition in older adults [67]. ...
6.2. Nutritional Supplementation with HMB
HMB is an active leucine metabolite which activates the mTOR signaling pathway in muscle. Following its absorption, dietary leucine is converted into α-ketoisocaproate (KIC), which is further metabolized into either isovaleryl-CoA or HMB. Under normal conditions, the majority of KIC is converted into isovaleryl-CoA, while only approximately 5% of leucine is metabolized to HMB. This implies that, in order to reach pharmacological levels of HMB, this compound needs to be administered directly, rather than via increasing leucine dosage. It has recently been suggested that HMB may be used to protect or restore muscle mass in older persons with reduced lean body mass [74].
HMB exerts its effects through protective, anticatabolic mechanisms and directly influences protein synthesis. HMB has also been shown to stabilize the muscle cell membrane, to modulate protein degradation and to up-regulate protein synthesis [68]. The daily administration of a nutritional mixture including HMB (2 g), arginine (5 g), and lysine (1.5 g) for 12 weeks was shown to improve physical performance, muscle strength, fat-free mass and protein synthesis in sedentary older women [74]. More recently, Deutz and colleagues [13]—in a multicenter, randomized, placebo-controlled, double-blind trial—demonstrated that the early administration (within 72 h of hospitalization) of a nutrient-dense oral nutritional supplement containing high concentrations of protein and HMB was associated with decreased post-discharge mortality and improved nutritional status in malnourished older adults [13].

[Nutrition_supplements_for_athletes_2014_review-14] Mullin GE (February 2014). "Nutrition supplements for athletes: potential application to malnutrition". Nutr. Clin. Pract. 29 (1): 146–147. doi:10.1177/0884533613516130. PMID 24336486.

[HMDB-15] "3-Hydroxyisovaleric acid". Human Metabolome Database. 11 February 2016. Retrieved 25 May 2016.

[Sarcopenia_July_2015_review-16] Phillips SM (July 2015). "Nutritional supplements in support of resistance exercise to counter age-related sarcopenia". Adv. Nutr. 6 (4): 452–460. doi:10.3945/an.115.008367. PMC 4496741. PMID 26178029.

[HMB_in_vivo_human_pharmacodynamics-17] Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ, Atherton PJ (June 2013). "Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism" (PDF). J. Physiol. (Lond.). 591 (11): 2911–2923. doi:10.1113/jphysiol.2013.253203. PMC 3690694. PMID 23551944. Retrieved 27 May 2016.

[HMB_in_animals_2015_review-18] Szcześniak KA, Ostaszewski P, Fuller JC, Ciecierska A, Sadkowski T (June 2015). "Dietary supplementation of β-hydroxy-β-methylbutyrate in animals - a review". J Anim Physiol Anim Nutr (Berl). 99 (3): 405–417. doi:10.1111/jpn.12234. PMID 25099672. Retrieved 1 June 2016. Cholesterol is a major component of the cell membrane, and sarcolemma is the one that relies mainly on de novo synthesis of cholesterol. This is important under stressful conditions when muscle cells may lack the capacity to produce adequate amounts of the cholesterol that is essential to proper functioning of cell membranes. Many biochemical studies have shown that HMB may be a precursor of cholesterol synthesis (Bachhawat et al., 1955; Bloch et al., 1954; Coon et al., 1955; Adamson and Greenberg, 1955; Gey et al., 1957). According to pertinent literature, HMB carbon is incorporated into cholesterol. Therefore, increased intramuscular HMB concentrations may provide readily available substrate for the cholesterol synthesis that is needed to form and stabilize the sarcolemma. ... In theory, HMB use as a precursor to cholesterol could aid in stabilizing muscle cell membranes; however, this has not been confirmed by research studies.

[Sarcopenia_May_2016_review-19] Landi F, Calvani R, Tosato M, Martone AM, Ortolani E, Savera G, D'Angelo E, Sisto A, Marzetti E (May 2016). "Protein Intake and Muscle Health in Old Age: From Biological Plausibility to Clinical Evidence". Nutrients. 8 (5): 295. doi:10.3390/nu8050295. PMC 4882708. PMID 27187465. HMB exerts its effects through protective, anticatabolic mechanisms and directly influences protein synthesis. HMB has also been shown to stabilize the muscle cell membrane, to modulate protein degradation and to up-regulate protein synthesis [68]. ... More recently, Deutz and colleagues [13]—in a multicenter, randomized, placebo-controlled, double-blind trial—demonstrated that the early administration (within 72 h of hospitalization) of a nutrient-dense oral nutritional supplement containing high concentrations of protein and HMB was associated with decreased post-discharge mortality and improved nutritional status in malnourished older adults [13].

[Skeletal_muscle_crosstalk_2016_review-20] ^ ^a ^b ^c ^d ^e ^f ^g ^h Argilés JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Mañas L (June 2016). "Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease". J. Am. Med. Dir. Assoc. 17 (9): 789–96. doi:10.1016/j.jamda.2016.04.019. PMID 27324808. Studies suggest dietary protein and leucine or its metabolite b-hydroxy b-methylbutyrate (HMB) can improve muscle function, in turn improving functional performance. ... These have identified the leucine metabolite β-hydroxy β-methylbutyrate (HMB) as a potent stimulator of protein synthesis as well as an inhibitor of protein breakdown in the extreme case of cachexia.^{65, 72, 76, 77, 78, 79, 80, 81, 82, 83, 84} A growing body of evidence suggests HMB may help slow, or even reverse, the muscle loss experienced in sarcopenia and improve measures of muscle strength.^{44, 65, 72, 76, 77, 78, 79, 80, 81, 82, 83, 84} However, dietary leucine does not provide a large amount of HMB: only a small portion, as little as 5%, of catabolized leucine is metabolized into HMB.⁸⁵ Thus, although dietary leucine itself can lead to a modest stimulation of protein synthesis by producing a small amount of HMB, direct ingestion of HMB more potently affects such signaling, resulting in demonstrable muscle mass accretion.^{71, 80} Indeed, a vast number of studies have found that supplementation of HMB to the diet may reverse some of the muscle loss seen in sarcopenia and in hypercatabolic disease.^{65, 72, 83, 86, 87} The overall treatment of muscle atrophy should include dietary supplementation with HMB, although the optimal dosage for each condition is still under investigation.⁶⁸ ...
Figure 4: Treatments for sarcopenia. It is currently recommended that patients at risk of or suffering from sarcopenia consume a diet high in protein, engage in resistance exercise, and take supplements of the leucine metabolite HMB. {{cite journal}}: External link in |quote= (help)

[Elderly_ICU_weakness_2014_review-21] Rahman A, Wilund K, Fitschen PJ, Jeejeebhoy K, Agarwala R, Drover JW, Mourtzakis M (July 2014). "Elderly persons with ICU-acquired weakness: the potential role for β-hydroxy-β-methylbutyrate (HMB) supplementation?". JPEN J. Parenter. Enteral Nutr. 38 (5): 567–575. doi:10.1177/0148607113502545. PMID 24072740. More than 20 publications in humans have demonstrated benefit with HMB supplementation associated with increased lean body mass without fat gain, improved markers of muscle strength, and decreased onset of muscle soreness with training and reduced markers of muscle damage.^5,29

[Molecular_Aspects_of_Medicine_2016_review-22] Cite error: The named reference Molecular Aspects of Medicine 2016 review was invoked but never defined (see the help page).

[PEDs_in_sports_2015_review-23] Cite error: The named reference PEDs in sports 2015 review was invoked but never defined (see the help page).

[HMB_athletic_performance-related_effects_2011_review-24] Cite error: The named reference HMB athletic performance-related effects 2011 review was invoked but never defined (see the help page).

[HMB_for_cancer_cachexia_2013_review-25] Cite error: The named reference HMB for cancer cachexia 2013 review was invoked but never defined (see the help page).

[Effects_of_amino_acid_derivatives_2015_review-26] Cite error: The named reference Effects of amino acid derivatives 2015 review was invoked but never defined (see the help page).

[Muscle_atrophy-related_signal_transduction_review-27] Cite error: The named reference Muscle atrophy-related signal transduction review was invoked but never defined (see the help page).

[Nutrition_supplements_for_athletes_2014_review-28] Cite error: The named reference Nutrition supplements for athletes 2014 review was invoked but never defined (see the help page).

[Leucine_metabolites_and_metabolism_2016_review-29] Duan Y, Li F, Li Y, Tang Y, Kong X, Feng Z, Anthony TG, Watford M, Hou Y, Wu G, Yin Y (January 2016). "The role of leucine and its metabolites in protein and energy metabolism". Amino Acids. 48 (1): 41–51. doi:10.1007/s00726-015-2067-1. PMID 26255285. S2CID 254080284.

[Cachexia_2016_systematic_review-30] Mochamat, Cuhls H, Marinova M, Kaasa S, Stieber C, Conrad R, Radbruch L, Mücke M (July 2016). "A systematic review on the role of vitamins, minerals, proteins, and other supplements for the treatment of cachexia in cancer: a European Palliative Care Research Centre cachexia project". Journal of Cachexia, Sarcopenia and Muscle. 8 (1): 25–39. doi:10.1002/jcsm.12127. PMC 5326814. PMID 27897391.

[HMB-dependent_Neuro2a_neurite_outgrowth-31] Salto R, Vílchez JD, Girón MD, Cabrera E, Campos N, Manzano M, Rueda R, López-Pedrosa JM (August 2015). "β-Hydroxy-β-Methylbutyrate (HMB) Promotes Neurite Outgrowth in Neuro2a Cells". PLOS ONE. 10 (8): e0135614. Bibcode:2015PLoSO..1035614S. doi:10.1371/journal.pone.0135614. PMC 4534402. PMID 26267903. In conclusion, we have shown for the first time that HMB promoted neurite outgrowth through PI3K/Akt and ERK1/2 signaling pathways in Neuro2a cells. Its effect in neuron differentiation is concomitant with higher levels of glucose transporters, the activation of mTOR by mTORC2 and consequently an increase in protein synthesis. Moreover, HMB is involved in promoting MEF2 activity and expression of members of this family of transcriptional factors. We believe that HMB may have great potential as [a neurotrophic] factor promoting neuron differentiation and plasticity. Our results indicated a novel effect of HMB on neurite outgrowth and call to further studies to reveal its positive influences on cognitive outcomes.

[Prevents_age-related_prefrontal_dendritic_pruning-32] Kougias DG, Nolan SO, Koss WA, Kim T, Hankosky ER, Gulley JM, Juraska JM (April 2016). "Beta-hydroxy-beta-methylbutyrate ameliorates aging effects in the dendritic tree of pyramidal neurons in the medial prefrontal cortex of both male and female rats". Neurobiol. Aging. 40: 78–85. doi:10.1016/j.neurobiolaging.2016.01.004. PMID 26973106. S2CID 3953100.

[Protein_synthesis_in_pig_peripheral_organs_and_brain-33] Kao M, Columbus DA, Suryawan A, Steinhoff-Wagner J, Hernandez-Garcia A, Nguyen HV, Fiorotto ML, Davis TA (May 2016). "Enteral β-Hydroxy-β-Methylbutyrate Supplementation Increases Protein Synthesis in Skeletal Muscle of Neonatal Pigs". Am. J. Physiol. Endocrinol. Metab. 310 (11): E1072–84. doi:10.1152/ajpendo.00520.2015. PMC 4935142. PMID 27143558. The fractional rates of protein synthesis in the brain were greater in the piglets supplemented with HMB 40 and 80 or fed the HP diet compared to feeding the LP diet alone or the fasting condition (P < 0.05, Fig. 5, G).

[The_neurology_of_mTOR-34] Lipton JO, Sahin M (October 2014). "The neurology of mTOR". Neuron. 84 (2): 275–291. doi:10.1016/j.neuron.2014.09.034. PMC 4223653. PMID 25374355.
Figure 2: The mTOR Signaling Pathway

[pmid27345321-35] Anthony TG (July 2016). "Mechanisms of protein balance in skeletal muscle". Domest. Anim. Endocrinol. 56 Suppl (Suppl): S23–S32. doi:10.1016/j.domaniend.2016.02.012. PMC 4926040. PMID 27345321.

[KIC_dioxygenase-36] "Homo sapiens: 4-hydroxyphenylpyruvate dioxygenase reaction". MetaCyc. SRI International. 20 August 2012. Retrieved 6 June 2016.

[Leucine_metabolism-37] Kohlmeier M (2015). "Leucine". Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. pp. 385–388. ISBN 9780123877840. Figure 8.57: Metabolism of L-leucine {{cite book}}: External link in |quote= (help)

[pmid21918059-38] Mock DM, Stratton SL, Horvath TD, Bogusiewicz A, Matthews NI, Henrich CL, Dawson AM, Spencer HJ, Owen SN, Boysen G, Moran JH (November 2011). "Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans". J. Nutr. 141 (11): 1925–1930. doi:10.3945/jn.111.146126. PMC 3192457. PMID 21918059. Reduced activity of MCC impairs catalysis of an essential step in the mitochondrial catabolism of the BCAA leucine. Metabolic impairment diverts methylcrotonyl CoA to 3-hydroxyisovaleryl CoA in a reaction catalyzed by enoyl-CoA hydratase (22, 23). 3-Hydroxyisovaleryl CoA accumulation can inhibit cellular respiration either directly or via effects on the ratios of acyl CoA:free CoA if further metabolism and detoxification of 3-hydroxyisovaleryl CoA does not occur (22). The transfer to carnitine by 4 carnitine acyl-CoA transferases distributed in subcellular compartments likely serves as an important reservoir for acyl moieties (39–41). 3-Hydroxyisovaleryl CoA is likely detoxified by carnitine acetyltransferase producing 3HIA-carnitine, which is transported across the inner mitochondrial membrane (and hence effectively out of the mitochondria) via carnitine-acylcarnitine translocase (39). 3HIA-carnitine is thought to be either directly deacylated by a hydrolase to 3HIA or to undergo a second CoA exchange to again form 3-hydroxyisovaleryl CoA followed by release of 3HIA and free CoA by a thioesterase.

[HMB_athletic_performance-related_effects_2011_review-39] Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (April 2011). "HMB supplementation: clinical and athletic performance-related effects and mechanisms of action". Amino Acids. 40 (4): 1015–1025. doi:10.1007/s00726-010-0678-0. PMID 20607321. S2CID 11120110. HMB is a metabolite of the amino acid leucine (Van Koverin and Nissen 1992), an essential amino acid. The first step in HMB metabolism is the reversible transamination of leucine to a-KIC that occurs mainly extrahepatically (Block and Buse 1990). Following this enzymatic reaction, a-KIC may follow one of two pathways. In the first, HMB is produced from a-KIC by the cytosolic enzyme KIC dioxygenase (Sabourin and Bieber 1983). The cytosolic dioxygenase has been characterized extensively and differs from the mitochondrial form in that the dioxygenase enzyme is a cytosolic enzyme, whereas the dehydrogenase enzyme is found exclusively in the mitochondrion (Sabourin and Bieber 1981, 1983). Importantly, this route of HMB formation is direct and completely dependent of liver KIC dioxygenase. Following this pathway, HMB in the cytosol is first converted to cytosolic b-hydroxy-b-methylglutaryl-CoA (HMG-CoA), which can then be directed for cholesterol synthesis (Rudney 1957) (Fig. 1). In fact, numerous biochemical studies have shown that HMB is a precursor of cholesterol (Zabin and Bloch 1951; Nissen et al. 2000).

In the second pathway, after transamination, a-KIC in liver generates isovaleryl-CoA through the enzymatic action of branched-chain ketoacid dehydrogenase (BCKD) and after several steps, there is production of HMG-CoA through the enzyme HMG-CoA synthase (Fig. 1). Under normal conditions the majority of KIC is converted into isovaleryl-CoA, in which approximately 5% of leucine is metabolized into HMB (Wilson et al. 2008; Van Koverin and Nissen 1992). However, Nissen and Abumrad (1997) provided evidence that the primary fate of HMB is probably conversion to HMG-CoA in the liver, for cholesterol biosynthesis.

[Lifestyle_medicine_WADA+NCAA-40] Rippe JM (2013). "Beta-Hydroxy beta-methylbutyrate". Lifestyle Medicine (2nd ed.). CRC Press. p. 724. ISBN 9781439845448. Retrieved 15 August 2016.

[WADA_banned_substances_list-41] "List of Prohibited Substances and Methods: By Substance". World Anti-Doping Agency. 2016. Retrieved 15 August 2016.

[3-Hydroxyisovaleric_acid_ChEBI_entry-42] "3-hydroxyisovaleric acid". Chemical Entities of Biological Interest. European Bioinformatics Institute. 23 October 2015. Retrieved 20 August 2016.

[3-Hydroxyisovalerate_ChEBI_entry-43] "3-hydroxyisovalerate". Chemical Entities of Biological Interest. European Bioinformatics Institute. 16 September 2014. Retrieved 20 August 2016.

[ISU_FY11_proposal-44] "The University of Iowa Economic Development Grow Iowa Values Fund Proposal: Fiscal Year 2011" (PDF). University of Iowa. pp. 13–16. Retrieved 1 September 2016.

[MTI_Pregnancy_statement-45] "Who should not take HMB?". Metabolic Technologies, Inc. Retrieved 23 August 2016. Pregnant or lactating women are advised against taking HMB because safety studies have not yet been conducted for these populations.

[May_2017_supplementation_review-46] Holeček M (May 2017). "Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions". Journal of Cachexia, Sarcopenia and Muscle. 8 (4): 529–541. doi:10.1002/jcsm.12208. PMC 5566641. PMID 28493406.

[Pimentel_2017_systematic_review_on_HMB-47] Silva VR, Belozo FL, Micheletti TO, Conrado M, Stout JR, Pimentel GD, Gonzalez AM (September 2017). "β-hydroxy-β-methylbutyrate free acid supplementation may improve recovery and muscle adaptations after resistance training: a systematic review". Nutrition Research. 45: 1–9. doi:10.1016/j.nutres.2017.07.008. hdl:11449/170023. PMID 29037326. HMB's mechanisms of action are generally considered to relate to its effect on both muscle protein synthesis and muscle protein breakdown (Figure 1) [2, 3]. HMB appears to stimulate muscle protein synthesis through an up-regulation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), a signaling cascade involved in coordination of translation initiation of muscle protein synthesis [2, 4]. Additionally, HMB may have antagonistic effects on the ubiquitin–proteasome pathway, a system that degrades intracellular proteins [5, 6]. Evidence also suggests that HMB promotes myogenic proliferation, differentiation, and cell fusion [7]. ... Exogenous HMB-FA administration has shown to increase intramuscular anabolic signaling, stimulate muscle protein synthesis, and attenuate muscle protein breakdown in humans [2].

[Pharmacological_targeting_2017_review-48] Weihrauch M, Handschin C (October 2017). "Pharmacological targeting of exercise adaptations in skeletal muscle: Benefits and pitfalls". Biochemical Pharmacology. 147: 211–220. doi:10.1016/j.bcp.2017.10.006. PMC 5850978. PMID 29061342.

[HMB_for_sarcopenia_and_sarcopenic_obesity_–_October_2017_review-49] Rossi AP, D'Introno A, Rubele S, Caliari C, Gattazzo S, Zoico E, Mazzali G, Fantin F, Zamboni M (October 2017). "The Potential of β-Hydroxy-β-Methylbutyrate as a New Strategy for the Management of Sarcopenia and Sarcopenic Obesity". Drugs & Aging. 34 (11): 833–840. doi:10.1007/s40266-017-0496-0. PMID 29086232. S2CID 4284897. Clinical trials performed in older adults confirm that HMB can attenuate the progression of sarcopenia in elderly subjects. HMB supplementation results in an increase in skeletal muscle mass and strength in the elderly and its effect is even greater when combined with physical exercise.

[HMB_clinical_evidence_in_sarcopenia_2017_review-50] Cruz-Jentoft AJ (May 2017). "Beta-hydroxy-beta-methyl butyrate (HMB): From experimental data to clinical evidence in sarcopenia". Current Protein & Peptide Science. 18 (7): 668–672. doi:10.2174/1389203718666170529105026. PMID 28554316. HMB is widely used as an ergogenic supplement by young athletes.

[Protein_synthesis_and_degradation_in_critical_illness_-_2017_review-51] Di Girolamo FG, Situlin R, Biolo G (March 2017). "What factors influence protein synthesis and degradation in critical illness?". Current Opinion in Clinical Nutrition and Metabolic Care. 20 (2): 124–130. doi:10.1097/MCO.0000000000000347. PMID 28002075. S2CID 3480306.

[Ergogenic_Aids_in_Sports_2017_review-52] tted - not planning to use this review

[Efficacy_and_safety_of_leucine_+_HMB_consumption-53] Borack MS, Volpi E (December 2016). "Efficacy and Safety of Leucine Supplementation in the Elderly". The Journal of Nutrition. 146 (12): 2625S–2629S. doi:10.3945/jn.116.230771. PMC 5118760. PMID 27934654. No serious side effects have been reported with leucine, EAA, or HMB supplementation; and the health risks associated with these supplements are few and predictable.

[Pharmacodynamics_and_pharmacokinetics_of_HMB-CA_in_humans_in_vivo-54] Wilkinson DJ, Hossain T, Limb MC, Phillips BE, Lund J, Williams JP, Brook MS, Cegielski J, Philp A, Ashcroft S, Rathmacher JA, Szewczyk NJ, Smith K, Atherton PJ (October 2017). "Impact of the calcium form of β-hydroxy-β-methylbutyrate upon human skeletal muscle protein metabolism". Clinical Nutrition (Edinburgh, Scotland). 37 (6): 2068–2075. doi:10.1016/j.clnu.2017.09.024. PMC 6295980. PMID 29097038. Ca-HMB led a significant and rapid (<60 min) peak in plasma HMB concentrations (483.6 ± 14.2 μM, p < 0.0001). This rise in plasma HMB was accompanied by increases in MPS (PA: 0.046 ± 0.004%/h, CaHMB: 0.072 ± 0.004%/h, p < [0.001]) and suppressions in MPB (PA: 7.6 ± 1.2 μmol Phe per leg min^-1, Ca-HMB: 5.2 ± 0.8 μmol Phe per leg min^-1, p < 0.01). ... During the first 2.5 h period we gathered postabsorptive/fasted measurements, the volunteers then consumed 3.42 g of Ca-HMB (equivalent to 2.74 g of FA-HMB) ... It may seem difficult for one to reconcile that acute provision of CaHMB, in the absence of exogenous nutrition (i.e. EAA's) and following an overnight fast, is still able to elicit a robust, perhaps near maximal stimulation of MPS, i.e. raising the question as to where the additional AA's substrates required for supporting this MPS response are coming from. It would appear that the AA's to support this response are derived from endogenous intracellular/plasma pools and/or protein breakdown (which will increase in fasted periods). ... To conclude, a large single oral dose (~3 g) of Ca-HMB robustly (near maximally) stimulates skeletal muscle anabolism, in the absence of additional nutrient intake; the anabolic effects of Ca-HMB are equivalent to FA-HMB, despite purported differences in bioavailability (Fig. 4).

[Pharmacology_of_HMB-FA_in_humans_in_vivo-55] Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ, Atherton PJ (June 2013). "Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism" (PDF). The Journal of Physiology. 591 (11): 2911–2923. doi:10.1113/jphysiol.2013.253203. PMC 3690694. PMID 23551944. The stimulation of MPS through mTORc1-signalling following HMB exposure is in agreement with pre-clinical studies (Eley et al. 2008). ... Furthermore, there was clear divergence in the amplitude of phosphorylation for 4EBP1 (at Thr37/46 and Ser65/Thr70) and p70S6K (Thr389) in response to both Leu and HMB, with the latter showing more pronounced and sustained phosphorylation. ... Nonetheless, as the overall MPS response was similar, this cellular signalling distinction did not translate into statistically distinguishable anabolic effects in our primary outcome measure of MPS. ... Interestingly, although orally supplied HMB produced no increase in plasma insulin, it caused a depression in MPB (−57%). Normally, postprandial decreases in MPB (of ~50%) are attributed to the nitrogen-sparing effects of insulin since clamping insulin at post-absorptive concentrations (5 μU ml⁻¹) while continuously infusing AAs (18 g h⁻¹) did not suppress MPB (Greenhaff et al. 2008), which is why we chose not to measure MPB in the Leu group, due to an anticipated hyperinsulinaemia (Fig. 3C). Thus, HMB reduces MPB in a fashion similar to, but independent of, insulin. These findings are in-line with reports of the anti-catabolic effects of HMB suppressing MPB in pre-clinical models, via attenuating proteasomal-mediated proteolysis in response to LPS (Eley et al. 2008).

[pmid21918059-56] Mock DM, Stratton SL, Horvath TD, Bogusiewicz A, Matthews NI, Henrich CL, Dawson AM, Spencer HJ, Owen SN, Boysen G, Moran JH (November 2011). "Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans". The Journal of Nutrition. 141 (11): 1925–1930. doi:10.3945/jn.111.146126. PMC 3192457. PMID 21918059. Reduced activity of MCC impairs catalysis of an essential step in the mitochondrial catabolism of the BCAA leucine. Metabolic impairment diverts methylcrotonyl CoA to 3-hydroxyisovaleryl CoA in a reaction catalyzed by enoyl-CoA hydratase (22, 23). 3-Hydroxyisovaleryl CoA accumulation can inhibit cellular respiration either directly or via effects on the ratios of acyl CoA:free CoA if further metabolism and detoxification of 3-hydroxyisovaleryl CoA does not occur (22). The transfer to carnitine by 4 carnitine acyl-CoA transferases distributed in subcellular compartments likely serves as an important reservoir for acyl moieties (39–41). 3-Hydroxyisovaleryl CoA is likely detoxified by carnitine acetyltransferase producing 3HIA-carnitine, which is transported across the inner mitochondrial membrane (and hence effectively out of the mitochondria) via carnitine-acylcarnitine translocase (39). 3HIA-carnitine is thought to be either directly deacylated by a hydrolase to 3HIA or to undergo a second CoA exchange to again form 3-hydroxyisovaleryl CoA followed by release of 3HIA and free CoA by a thioesterase.

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