View source for Β-Hydroxy β-methylbutyric acid

{{short description|Chemical compound}}
{{featured article}}
{{Distinguish|β-Hydroxybutyric acid}}
{{Use dmy dates|date=November 2018}}
{{lowercase title}}
{{Infobox drug
|verifiedrevid = 718190677
|drug_name = β-Hydroxy β-methylbutyric acid
|INN = none
|IUPAC_name = 3-hydroxy-3-methylbutanoic acid
|image = Beta-Hydroxy beta-methylbutyric acid 2.svg
|alt = Structural formula, conjugate acid
|image2 = Beta-Hydroxy beta-methylbutyrate 2.svg
|alt2 = Structural formula, conjugate base
|caption = Top: β-Hydroxy β-methylbutyric acid<br />Bottom: β-Hydroxy β-methylbutyrate
<!-- Clinical data -->
|licence_EU = <!-- EMA requires brand name -->
|licence_US = <!-- FDA may use generic name -->
|pregnancy_AU = <!-- A/B1/B2/B3/C/D/X -->
|pregnancy_US = <!-- A / B / C / D / X / N -->
|routes_of_administration = [[Oral administration|By mouth]]<ref name="ISSN position stand 2013" /><!--This ref refers to "ingestion" of HMB a number of times--> or [[Feeding tube#Types|nasogastric]]<ref name="Ensure and Juven" />
|legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
|legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
|legal_DE = <!-- Anlage I, II, III or Unscheduled-->
|legal_NZ = <!-- Class A, B, C -->
|legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
|legal_US = Dietary supplement
|legal_UN = Unscheduled
<!-- Pharmacokinetic data -->
|metabolites = [[HMB-CoA]], [[HMG-CoA]], [[mevalonate]], [[cholesterol]], [[acetyl-CoA]], [[acetoacetate]], [[β-hydroxybutyrate]]
|onset = {{abbr|HMB-FA|β-hydroxy β-methylbutyric acid}}: 30–60&nbsp;minutes<ref name="ISSN position stand 2013"/><br />{{abbr|HMB-Ca|calcium β-hydroxy β-methylbutyrate monohydrate}}: 1–2&nbsp;hours<ref name="ISSN position stand 2013"/>
|elimination_half-life = {{abbr|HMB-FA|β-hydroxy β-methylbutyric acid}}: 3&nbsp;hours<ref name="ISSN position stand 2013"/><br />{{abbr|HMB-Ca|calcium β-hydroxy β-methylbutyrate monohydrate}}: 2.5&nbsp;hours<ref name="ISSN position stand 2013"/>
|excretion = [[Renal]] (10–40% excreted)<ref name="ISSN position stand 2013">{{cite journal | vauthors = 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 | title = International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB) | journal = Journal of the International Society of Sports Nutrition | volume = 10 | issue = 1 | pages = 6 | date = February 2013 | pmid = 23374455 | pmc = 3568064 | doi = 10.1186/1550-2783-10-6 | quote = The [International Society of Sports Nutrition] has concluded the following.  1. HMB can be used to enhance recovery by attenuating exercise induced skeletal muscle damage in trained and untrained populations.&nbsp;... 4. Thirty-eight mg·kg·BM<sup>−1</sup> 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.&nbsp;... 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. | doi-access = free }}</ref><ref name="HMB athletic performance-related effects 2011 review" />
<!-- Identifiers -->
|CAS_number = 625-08-1
|CAS_number_Ref = {{cascite|correct|}}
|ATC_prefix = none
|PubChem = 69362
|ChemSpiderID = 62571
|ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
|UNII = 3F752311CD
|UNII_Ref = {{fdacite|correct|FDA}}
|KEGG = C20827
|KEGG_Ref = {{keggcite|correct|kegg}}
|ChEBI = 37084
|ChEBI_Ref = {{ebicite|correct|}}
|synonyms = [[Conjugate acid]] form:<br />β-hydroxyisovaleric acid<br />3-hydroxyisovaleric acid<br />[[Conjugate base]] form:<br />hydroxymethylbutyrate
<!-- Chemical data -->
|C=5 | H=10 | O=3
|SMILES = CC(C)(CC(=O)O)O
|StdInChI_Ref = {{stdinchicite|correct|chemspider}}
|StdInChI = 1S/C5H10O3/c1-5(2,8)3-4(6)7/h8H,3H2,1-2H3,(H,6,7)
|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
|StdInChIKey = AXFYFNCPONWUHW-UHFFFAOYSA-N
|density = ~1.1
|density_notes = at 20&nbsp;°C<ref name="HMB MSDS">{{cite web|title=Safety data sheet: 3-Hydroxy-3-methyl butyric acid|url=http://www.alfachina.cn/AlfaAesarApp/getpdf?contentId=EN_US_MSDS_42722|publisher=Alfa Aesar|access-date=9 November 2016|date=23 March 2005|url-status=live|archive-url=https://web.archive.org/web/20160917215449/http://www.alfachina.cn/AlfaAesarApp/getpdf?contentId=EN_US_MSDS_42722|archive-date=17 September 2016}}</ref>
|melting_point = −80
|melting_notes = (glass)<ref name = "Coffman_1958"/>
|boiling_point = 128
|boiling_notes = at 7&nbsp;[[Millimeter of mercury|mmHg]]<ref name="HMB MSDS" /><ref name="ChemSpider">{{cite encyclopedia | chapter=3-OH-isovaleric acid | url=http://www.chemspider.com/Chemical-Structure.62571.html | title=ChemSpider | date=2015 | publisher=Royal Society of Chemistry | access-date=10 August 2016 | quote=Experimental Boiling Point:&nbsp;... 128&nbsp;°C / 7&nbsp;mm&nbsp;...<br />Experimental solubility:<br />Soluble in water | url-status=live | archive-url=https://web.archive.org/web/20160811095753/http://www.chemspider.com/Chemical-Structure.62571.html | archive-date=11 August 2016}}</ref>
}}

'''β-Hydroxy β-methylbutyric acid'''{{#tag:ref|Synonyms and alternate spellings include: '''{{nowrap|''beta''-hydroxy}} {{nowrap|''beta''-methylbutyric}} acid''', '''{{nowrap|3-hydroxy-3-methylbutanoic}} acid''' ([[International Union of Pure and Applied Chemistry|IUPAC]] name), '''{{nowrap|3-hydroxyisovaleric}} acid''', and '''{{nowrap|''beta''-hydroxyisovaleric}} acid'''.<ref name="PubChem HMB">{{cite encyclopedia | chapter = beta-Hydroxyisovaleric acid | url = https://pubchem.ncbi.nlm.nih.gov/compound/69362 | title = PubChem Compound | publisher = United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | access-date = 6 February 2018 | date = 3 February 2018 | quote = Chemical Names: Beta-Hydroxyisovaleric acid; 3-Hydroxy-3-methylbutanoic acid;&nbsp;... 3-Hydroxyisovaleric acid; 3-Hydroxy-3-methylbutyric acid | url-status = live | archive-url = https://web.archive.org/web/20180206190322/https://pubchem.ncbi.nlm.nih.gov/compound/69362 | archive-date = 6 February 2018}}</ref>| group = "note"}} ('''HMB'''), otherwise known as its [[conjugate base]], '''{{nowrap|β-hydroxy}} {{nowrap|β-methylbutyrate}}''', is a [[natural product|naturally produced]] substance in humans that is used as a [[dietary supplement]] and as an ingredient in certain [[medical food]]s that are intended to promote [[wound healing]] and provide nutritional support for people with [[muscle atrophy|muscle wasting]] due to [[cancer]] or [[HIV/AIDS]].{{#tag:ref|<ref name="ISSN position stand 2013" /><ref name="Iowa State University" /><ref name="Medical foods" /><ref name="PR Newswire" />|group="sources"}} In healthy adults, supplementation with HMB has been shown to increase exercise-induced gains in [[muscle]] size, muscle strength, and [[lean body mass]], reduce [[skeletal muscle]] damage from exercise, improve aerobic exercise performance, and expedite recovery from exercise.<ref name="Enhancing performance" group="sources"/> [[Literature review|Medical reviews]] and [[Meta-analysis|meta-analyses]] indicate that HMB supplementation also helps to preserve or increase lean body mass and muscle strength in individuals experiencing [[sarcopenia|age-related muscle loss]].<ref name="Meta-analysis of efficacy in older adults" group="note" /><ref name="Meta-analytic systematic review September 2015" /><ref name="August 2017 supplementation review" /><ref name="HMB for sarcopenia and sarcopenic obesity – October 2017 review" /> HMB produces these effects in part by stimulating the [[protein synthesis|production of proteins]] and inhibiting the [[protein breakdown|breakdown of proteins]] in muscle tissue.<ref name="Meta-analytic systematic review September 2015" /><ref name="Pimentel 2017 systematic review on HMB"/><ref name="Pharmacology of HMB-FA in humans in vivo" /> No [[adverse effect]]s from long-term use as a dietary supplement in adults have been found.<ref name="Molecular Aspects of Medicine 2016 review"/><ref name="Systematic review December 2013"/><ref name="Efficacy and safety of leucine + HMB consumption"/>

The effects of HMB on human skeletal muscle were first discovered by Steven L. Nissen at [[Iowa State University]] in the {{nowrap|mid-1990s}}.<ref name="Iowa State University" /><ref name="Discovered" /> {{As of|2018|post=,}} HMB has not been banned by the [[National Collegiate Athletic Association]], [[World Anti-Doping Agency]], or any other prominent national or international athletic organization.<ref name="Lifestyle medicine WADA+NCAA" /><ref name="WADA banned substances list" /><ref name="NCAA banned substances list" /> In 2006, only about 2% of college [[student athlete]]s in the United States used HMB as a dietary supplement.<ref name="PEDs in sports 2015 review" /><ref name="NCAA 2006 study" /> As of 2017, HMB has reportedly found widespread use as an [[ergogenic supplement]] among young athletes.<ref name="HMB clinical evidence in sarcopenia 2017 review" />

==Uses==
===Available forms===

HMB is sold as an [[over-the-counter]] [[dietary supplement]] in the [[free acid]] form, ''β-hydroxy β-methylbutyric acid'' (HMB-FA), and as a [[monohydrate]]d calcium [[salt (chemistry)|salt]] of the [[conjugate base]], ''calcium {{nowrap|β-hydroxy β-methylbutyrate}} monohydrate'' (HMB-Ca, CaHMB).<ref name="PEDs in sports 2015 review">{{cite journal | vauthors = Momaya A, Fawal M, Estes R | title = Performance-enhancing substances in sports: a review of the literature | journal = Sports Medicine | volume = 45 | issue = 4 | pages = 517–531 | date = April 2015 | pmid = 25663250 | doi = 10.1007/s40279-015-0308-9 | s2cid = 45124293 | quote = Currently, HMB is available as an over-the-counter supplement. The drug is not tested for nor banned by any sporting organization.&nbsp;... 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.&nbsp;... 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].&nbsp;... No serious adverse effects from HMB consumption have been reported. }}</ref><ref name="HMB-FA commercial availability as of 2015">{{cite journal | vauthors = Fuller JC, Sharp RL, Angus HF, Khoo PY, Rathmacher JA | title = Comparison of availability and plasma clearance rates of β-hydroxy-β-methylbutyrate delivery in the free acid and calcium salt forms | journal = The British Journal of Nutrition | volume = 114 | issue = 9 | pages = 1403–1409 | date = November 2015 | pmid = 26373270 | doi = 10.1017/S0007114515003050 | department = primary source | quote = Recently, the free acid form of HMB (HMB-FA) has become commercially available in capsule form (gelcap). The current study was conducted to compare the bioavailability of HMB using the two commercially available capsule forms of HMB-FA and Ca-HMB.&nbsp;... In conclusion, HMB-FA in capsule form improves clearance rate and availability of HMB compared with Ca-HMB in capsule form. | doi-access = free }}</ref> Since only a small fraction of HMB's metabolic precursor, {{nowrap|{{smallcaps all|L}}-leucine}}, is metabolized into HMB, pharmacologically active concentrations of the compound in [[blood plasma]] and muscle can only be achieved by supplementing HMB directly.<ref name="ISSN position stand 2013" /><ref name="Skeletal muscle crosstalk 2016 review" /><ref name="HMB clinical evidence 2016 review">{{cite journal | vauthors = Landi F, Calvani R, Tosato M, Martone AM, Ortolani E, Savera G, D'Angelo E, Sisto A, Marzetti E | title = Protein Intake and Muscle Health in Old Age: From Biological Plausibility to Clinical Evidence | journal = Nutrients | volume = 8 | issue = 5 | pages = 295 | date = May 2016 | pmid = 27187465 | pmc = 4882708 | doi = 10.3390/nu8050295 | quote = 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.&nbsp;... 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].<!--&nbsp;... 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].--> | doi-access = free}}</ref> A healthy adult produces approximately 0.3&nbsp;grams per day, while supplemental HMB is usually taken in doses of {{nowrap|3–6}}&nbsp;grams per day.<ref name="Systematic review December 2013">{{cite journal | vauthors = Molfino A, Gioia G, Rossi Fanelli F, Muscaritoli M | title = Beta-hydroxy-beta-methylbutyrate supplementation in health and disease: a systematic review of randomized trials | journal = Amino Acids | volume = 45 | issue = 6 | pages = 1273–1292 | date = December 2013 | pmid = 24057808 | doi = 10.1007/s00726-013-1592-z | hdl = 11573/524784 | s2cid = 8688823 | quote = Normally, an individual metabolizes 60&nbsp;g of L-LEU to obtain 3&nbsp;g of HMB but a 70&nbsp;kg person produces 0.2–0.4&nbsp;g of HMB per day, depending on the dose of LEU in the diet (Van Koevering and Nissen 1992).&nbsp;... The usual dose of 3&nbsp;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.&nbsp;... These results show that HMB/ARG/GLN can be safely used to treat AIDS- and cancer-related muscle wasting | doi-access = free }}</ref> HMB is sold at a cost of about {{nowrap|{{currency|30|USD}}–50}} per month when taken in doses of 3&nbsp;grams per day.<ref name="Molecular Aspects of Medicine 2016 review" /> HMB is also contained in several nutritional products and medical foods marketed by [[Abbott Laboratories]] (e.g., certain formulations of [[Ensure]] and [[Juven]]),<ref name="Iowa State University">{{cite web|vauthors=Linn J|title=Proteins in Human Health and Performance|url=http://www.fshn.hs.iastate.edu/proteins-in-human-health-and-performance/|archive-url=https://web.archive.org/web/20160827191643/http://www.fshn.hs.iastate.edu/proteins-in-human-health-and-performance/|archive-date=27 August 2016|publisher=Iowa State University|access-date=31 July 2016|date=13 May 2013|quote=Dr. Nissen and his collaborator Dr. Naji N. Abumrad, Professor and Chair, Department of Surgery, Vanderbilt University, discovered beta-hydroxy-beta-methylbutyrate (HMB) and its beneficial effects on human health and performance. HMB is currently marketed nationally by Abbott Laboratories as Revigor™, which is a component of Ensure® Muscle Health, and Juven®, which is a nutritional beverage that is clinically shown to promote healing after injury or surgery.|url-status=dead}}</ref><ref name="Abbott Nutrition product overview" /> and is present in insignificant quantities in certain foods, such as [[alfalfa]], [[asparagus]], [[avocado]]s, [[cauliflower]], [[grapefruit]], and [[catfish]].<ref name="2008rev">{{cite journal | vauthors = Wilson GJ, Wilson JM, Manninen AH | title = Effects of beta-hydroxy-beta-methylbutyrate (HMB) on exercise performance and body composition across varying levels of age, sex, and training experience: A review | journal = Nutrition & Metabolism | volume = 5 | pages = 1 | date = January 2008 | pmid = 18173841 | pmc = 2245953 | doi = 10.1186/1743-7075-5-1 |doi-access=free }}</ref><ref name="HMB in animals 2015 review"/>

===Medical===
Supplemental HMB has been used in [[clinical trial]]s as a treatment for preserving lean body mass in muscle wasting conditions, particularly [[sarcopenia]], and has been studied in clinical trials as an [[adjunct therapy]] in conjunction with [[resistance exercise]].<ref name="Meta-analytic systematic review September 2015" /><ref name="Molecular Aspects of Medicine 2016 review" /><ref name="Skeletal muscle crosstalk 2016 review" /> Based upon two medical reviews and a [[meta-analysis]] of seven [[randomized controlled trial]]s, HMB supplementation can preserve or increase lean muscle mass and muscle strength in [[sarcopenic]] older adults.{{#tag:ref|The meta-analysis found that the average increase in muscle mass due to HMB supplementation in older adults was {{convert|0.35|kg|lbs}}.<ref name="Meta-analytic systematic review September 2015" /> The [[95%&nbsp;confidence interval]] for the estimated increase in muscle mass due to HMB supplementation is {{convert|0.11|–|0.59|kg|lb}}.<ref name="Meta-analytic systematic review September 2015" /><br />The seven randomized controlled trials that were included in the meta-analysis contained a total of 147&nbsp;older adults in the HMB [[Treatment and control groups|treatment groups]] and 140&nbsp;older adults in the [[Treatment and control groups|control groups]].<ref name="Meta-analytic systematic review September 2015" /> The seven trials had durations of 2–11&nbsp;months and the average duration of the studies, [[weighted average|weighted by their sample size]], was approximately 6&nbsp;months.<ref name="Meta-analytic systematic review September 2015" />|name="Meta-analysis of efficacy in older adults"|group="note"}}<ref name="Meta-analytic systematic review September 2015">{{cite journal | vauthors = Wu H, Xia Y, Jiang J, Du H, Guo X, Liu X, Li C, Huang G, Niu K | title = Effect of beta-hydroxy-beta-methylbutyrate supplementation on muscle loss in older adults: a systematic review and meta-analysis | journal = Archives of Gerontology and Geriatrics | volume = 61 | issue = 2 | pages = 168–175 | date = September 2015 | pmid = 26169182 | doi = 10.1016/j.archger.2015.06.020 | quote = 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.&nbsp;... Mechanisms underlying the role of HMB in muscle regeneration have also been explored: results indicated that HMB enhances protein synthesis via upregulation of anabolic signaling pathways and attenuate proteolysis via downregulation of catabolic signaling pathways (Wilkinson et al., 2013). }}</ref><ref name="August 2017 supplementation review">{{cite journal | vauthors = Holeček M | title = Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions | journal = Journal of Cachexia, Sarcopenia and Muscle | volume = 8 | issue = 4 | pages = 529–541 | date = August 2017 | pmid = 28493406 | pmc = 5566641 | doi = 10.1002/jcsm.12208 | quote = 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.&nbsp;... 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. }}</ref><ref name="HMB for sarcopenia and sarcopenic obesity – October 2017 review">{{cite journal | vauthors = Rossi AP, D'Introno A, Rubele S, Caliari C, Gattazzo S, Zoico E, Mazzali G, Fantin F, Zamboni M | title = The Potential of β-Hydroxy-β-Methylbutyrate as a New Strategy for the Management of Sarcopenia and Sarcopenic Obesity | journal = Drugs & Aging | volume = 34| issue = 11| pages = 833–840| date = October 2017 | pmid = 29086232 | doi = 10.1007/s40266-017-0496-0 | s2cid = 4284897 | quote = 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.}}</ref> HMB does not appear to significantly affect fat mass in older adults.<ref name="Meta-analytic systematic review September 2015" /><ref name="August 2017 supplementation review" /> Preliminary clinical evidence suggests that HMB supplementation may also prevent [[muscle atrophy]] during [[bed rest]].<ref name="Meta-analytic systematic review September 2015" /><ref name="HMB clinical evidence in sarcopenia 2017 review" /> A growing body of evidence supports the efficacy of HMB in nutritional support for reducing, or even reversing, the loss of muscle mass, [[Muscle#Physiology|muscle function]], and [[Muscle#Strength|muscle strength]] that occurs in [[hypercatabolic]] disease states such as cancer [[cachexia]];<ref name="Molecular Aspects of Medicine 2016 review" /><ref name="Skeletal muscle crosstalk 2016 review">{{cite journal | vauthors = Argilés JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Mañas L | title = Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease | journal = Journal of the American Medical Directors Association | volume = 17 | issue = 9 | pages = 789–796 | date = September 2016 | pmid = 27324808 | doi = 10.1016/j.jamda.2016.04.019 | url = http://www.jamda.com/article/S1525-8610(16)30113-X/fulltext | quote = Studies suggest dietary protein and leucine or its metabolite β-hydroxy β-methylbutyrate (HMB) can improve muscle function, in turn improving functional performance.&nbsp;... 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.&nbsp;... 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.&nbsp;... 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.&nbsp;... 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.&nbsp;... 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.&nbsp;... The overall treatment of muscle atrophy should include dietary supplementation with HMB, although the optimal dosage for each condition is still under investigation.&nbsp;...<br /> 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. | doi-access = free }}</ref><ref name="Nutrition supplements for athletes 2014 review">{{cite journal | vauthors = Mullin GE | title = Nutrition supplements for athletes: potential application to malnutrition | journal = Nutrition in Clinical Practice | volume = 29 | issue = 1 | pages = 146–147 | date = February 2014 | pmid = 24336486 | doi = 10.1177/0884533613516130 | quote = There are a number of nutrition products on the market that are touted to improve sports performance. HMB appears to be the most promising and to have clinical applications to improve muscle mass and function. Continued research using this nutraceutical to prevent and/or improve malnutrition in the setting of muscle wasting is warranted. }}</ref> consequently, the authors of two 2016 reviews of the clinical evidence recommended that the prevention and treatment of sarcopenia and muscle wasting in general include supplementation with HMB, regular resistance exercise, and consumption of a [[high-protein diet]].<ref name="Molecular Aspects of Medicine 2016 review" /><ref name="Skeletal muscle crosstalk 2016 review" />

Clinical trials that used HMB for the treatment of muscle wasting have involved the administration of 3&nbsp;grams of HMB per day under different dosing regimens.<ref name="Molecular Aspects of Medicine 2016 review" /> According to one review, an optimal dosing regimen is to administer it in one 1&nbsp;gram dose, three times a day, since this ensures elevated plasma concentrations of HMB throughout the day;<ref name="Molecular Aspects of Medicine 2016 review" /> however, {{as of|2016|lc=y}} the best dosing regimen for muscle wasting conditions is still being investigated.<ref name="Skeletal muscle crosstalk 2016 review" />

Some branded products that contain HMB (i.e., certain formulations of Ensure and Juven) are [[medical food]]s that are intended to be used to provide nutritional support under the care of a doctor in individuals with [[muscle wasting]] due to [[HIV/AIDS]] or [[cancer]], to promote [[wound healing]] following surgery or injury, or when otherwise recommended by a medical professional.{{#tag:ref|<ref name="Ensure and Juven">{{cite web|title=Product Information: Ensure Enlive Advanced Therapeutic Nutrition Shake|publisher=Abbott Nutrition|url=http://static.abbottnutrition.com/cms-prod/abbottnutrition.com/img/Ensure-Enlive-Advanced-Therapeutic-Nutrition-Shake.pdf|access-date=22 August 2016|date=9 August 2016|quote=<br />{{•}}Use under medical supervision.<br />{{•}}HMB + protein for muscle health.|url-status=live|archive-url=https://web.archive.org/web/20161012132214/http://static.abbottnutrition.com/cms-prod/abbottnutrition.com/img/Ensure-Enlive-Advanced-Therapeutic-Nutrition-Shake.pdf|archive-date=12 October 2016}}<br /><br />{{cite web|title=Product Information: Juven|publisher=Abbott Nutrition|url=http://static.abbottnutrition.com/cms-prod/abbottnutrition.com/img/Juven.pdf|date=7 May 2016|access-date=22 August 2016|quote=<br />{{•}}Administer orally or as a modular via feeding tube&nbsp;...<br />{{•}}Use under medical supervision.<br />{{•}}Nutravigor® (CaHMB, calcium β-hydroxy-β-methylbutyrate)|url-status=live|archive-url=https://web.archive.org/web/20161012132216/http://static.abbottnutrition.com/cms-prod/abbottnutrition.com/img/Juven.pdf|archive-date=12 October 2016}}</ref><ref name="Iowa State University" /><ref name="Medical foods">{{cite journal | vauthors = Khamsi R | title = Rethinking the formula | journal = Nature Medicine | volume = 19 | issue = 5 | pages = 525–529 | date = May 2013 | pmid = 23652097 | doi = 10.1038/nm0513-525 | s2cid = 205379191 | quote = The questions about what defines a medical food will likely grow as the market does—and that market now extends far beyond PKU and other inherited metabolic disorders.&nbsp;... Abbott Nutrition's Juven provides nutrients to people with HIV or AIDS experiencing excessive weight loss due to disease | doi-access = free }}</ref><ref name="PR Newswire">{{cite web|title=JUVEN Added to Abbott Laboratories' Nutritional Product Line for People With Cancer, HIV/AIDS and Wounds/Pressure Ulcers|url=http://www.prnewswire.com/news-releases/juven-added-to-abbott-laboratories-nutritional-product-line-for-people-with-cancer-hivaids-and-woundspressure-ulcers-72059102.html|website=PR Newswire|publisher=Abbott Laboratories|access-date=11 December 2016|date=12 March 2004|url-status=dead|archive-url=https://web.archive.org/web/20161220105220/http://www.prnewswire.com/news-releases/juven-added-to-abbott-laboratories-nutritional-product-line-for-people-with-cancer-hivaids-and-woundspressure-ulcers-72059102.html|archive-date=20 December 2016}}</ref>|group="sources"}} Juven, a nutrition product which contains 3&nbsp;grams of {{abbr|HMB-Ca|calcium β-hydroxy β-methylbutyrate monohydrate}}, 14&nbsp;grams of [[arginine|{{smallcaps all|L}}-arginine]], and 14&nbsp;grams of [[glutamine|{{smallcaps all|L}}-glutamine]] per two servings,<ref name="Ensure and Juven" /> has been shown to improve [[lean body mass]] during clinical trials in individuals with AIDS and cancer, but not [[rheumatoid arthritis|rheumatoid cachexia]].<ref name="Systematic review December 2013" /><ref name="Sarcopenia and cachexia 2016 review" /><ref name="Elderly ICU weakness 2014 review">{{cite journal | vauthors = Rahman A, Wilund K, Fitschen PJ, Jeejeebhoy K, Agarwala R, Drover JW, Mourtzakis M | title = Elderly persons with ICU-acquired weakness: the potential role for β-hydroxy-β-methylbutyrate (HMB) supplementation? | journal = Journal of Parenteral and Enteral Nutrition | volume = 38 | issue = 5 | pages = 567–575 | date = July 2014 | pmid = 24072740 | doi = 10.1177/0148607113502545 | quote = 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.&nbsp;... One proposed cellular mechanism for HMB is principally through stabilization of the cholesterol membrane in muscle cells. HMB is metabolized to β-hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA) in the cytosol of muscle cells, which in turn is converted to cholesterol.&nbsp;... Muscle produces its own cholesterol to maintain the integrity of the cell membrane, typically from HMG-CoA, because it cannot supply its cholesterol needs via absorption from the circulation.| doi-access = free }}</ref> Further research involving the treatment of cancer cachexia with Juven over a period of several months is required to adequately determine treatment efficacy.<ref name="Systematic review December 2013" /><ref name="Sarcopenia and cachexia 2016 review">{{cite journal | vauthors = Mochamat, Cuhls H, Marinova M, Kaasa S, Stieber C, Conrad R, Radbruch L, Mücke M | title = 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 = Journal of Cachexia, Sarcopenia and Muscle | volume = 8| issue = 1| pages = 25–39| date = July 2016 | pmid = 27897391 | pmc = 5326814 | doi = 10.1002/jcsm.12127 | quote = Looking at studies with proteins and other dietary supplements the combination of HMB, arginine, and glutamine showed interesting results&nbsp;... In one study, 32&nbsp;patients gained an average of about 2&nbsp;kg of body weight.[21] This study was one of three studies confirming the positive effects of this combination in a variety of diagnoses/conditions such as HIV/AIDS patients and healthy adults.[40] Another study, on a far larger sample base of around 470&nbsp;cancer patients, found no significant difference with regard to LBM after 8&nbsp;weeks however a strong trend in the direction of an increase in LBM as measured by both bio-impedance and skin-fold measurements.[22] In summary, the effect of the combination of HMB, arginine, and glutamine on weight gain should be investigated in further studies on cancer patients investigating time periods of several months.}}</ref>

===Enhancing performance===
[[File:Calcium β-hydroxy β-methylbutyrate monohydrate.jpg|thumb|right|290px|A commercially available formulation of HMB. Each [[Capsule (pharmacy)#Standard sizes of two-piece capsules|size&nbsp;000 gelatin capsule]] contains 1&nbsp;gram of {{abbr|HMB-Ca|calcium β-hydroxy β-methylbutyrate monohydrate}} and an unspecified amount of [[microcrystalline cellulose]] and [[magnesium stearate]].|alt=An image of a commercially available HMB supplement]]
With an appropriate exercise program, dietary supplementation with 3&nbsp;grams of HMB per day has been shown to increase exercise-induced gains in muscle size,<!--<ref name="ISSN position stand 2013" /><ref name="Meta-analytic systematic review September 2015" /><ref name="August 2017 supplementation review" /><ref name="Pimentel 2017 systematic review on HMB" />--> muscle strength and power,<!--<ref name="August 2017 supplementation review" /><ref name="Effects of amino acid derivatives 2015 review" /><ref name="Pimentel 2017 systematic review on HMB" />--> and lean body mass,<!--<ref name="Effects of amino acid derivatives 2015 review" /><ref name="Pimentel 2017 systematic review on HMB" /><ref name="PEDs in sports 2015 review" />--> reduce exercise-induced skeletal muscle damage,{{#tag:ref|The effect of HMB on skeletal muscle damage has been assessed in studies on humans using four different [[Biomarker (medicine)|biomarkers]] of muscle damage or protein breakdown: [[blood serum|serum]] [[creatine kinase]], serum [[lactate dehydrogenase]], urinary [[urea nitrogen]], and urinary {{nowrap|[[3-methylhistidine]]}}.<ref name="ISSN position stand 2013" /><ref name="PEDs in sports 2015 review" /><ref name="Effects of amino acid derivatives 2015 review" /> When exercise intensity and volume are sufficient to cause skeletal muscle damage, such as during [[long-distance running]] or [[progressive overload]], HMB supplementation has been demonstrated to attenuate the rise in these biomarkers by 20–60%.<ref name="ISSN position stand 2013" /><ref name="PEDs in sports 2015 review" /><ref name="Exercise-Induced Muscle Damage Meta-analysis" />|group="note"|name="biomarkers"}}<!--<ref name="August 2017 supplementation review" /><ref name="Effects of amino acid derivatives 2015 review" /><ref name="Pimentel 2017 systematic review on HMB" /><ref name="PEDs in sports 2015 review" />--> and expedite recovery<!--<ref name="ISSN position stand 2013" /><ref name="August 2017 supplementation review" /><ref name="Pimentel 2017 systematic review on HMB" /><ref name="PEDs in sports 2015 review" />--> from high-intensity exercise.{{#tag:ref|<ref name="ISSN position stand 2013" /><ref name="Meta-analytic systematic review September 2015" /><ref name="August 2017 supplementation review" /><ref name="Pimentel 2017 systematic review on HMB" /><ref name="PEDs in sports 2015 review" /><ref name="Effects of amino acid derivatives 2015 review">{{cite journal | vauthors = Luckose F, Pandey MC, Radhakrishna K | title = Effects of amino acid derivatives on physical, mental, and physiological activities | journal = Critical Reviews in Food Science and Nutrition | volume = 55 | issue = 13 | pages = 1793–1807 | date = 2015 | pmid = 24279396 | doi = 10.1080/10408398.2012.708368 | s2cid = 22657268 | quote = HMB, a derivative of leucine, prevents muscle damage and increases muscle strength by reducing exercise-induced proteolysis in muscles and also helps in increasing lean body mass.&nbsp;... HMB is converted to HMB-CoA which is then used for the synthesis of cholesterol in muscle cells (Nissen and Abumrad, 1997). Cholesterol is needed for the growth, repair, and stabilization of cellular membranes during exercise (Chen, 1984).&nbsp;... The meta analysis studies and the individual studies conducted support the use of HMB as an effective aid to increase body strength, body composition, and to prevent muscle damage during resistance training. }}</ref><ref name="Exercise-Induced Muscle Damage Meta-analysis">{{cite journal | vauthors = Rahimi MH, Mohammadi H, Eshaghi H, Askari G, Miraghajani M | title = The Effects of Beta-Hydroxy-Beta-Methylbutyrate Supplementation on Recovery Following Exercise-Induced Muscle Damage: A Systematic Review and Meta-Analysis | journal = Journal of the American College of Nutrition | volume = 37 | issue = 7 | pages = 640–649 | date = 2018 | pmid = 29676656 | doi = 10.1080/07315724.2018.1451789 | s2cid = 4991601 | quote = The current evidence revealed a time-dependent effect of HMB in reducing LDH and CK serum levels among adults. HMB, therefore, may be seen as a priority muscle damage recovery agent in interventions.}}</ref>|group="sources"|name="Enhancing performance"}} Based upon limited clinical research, HMB supplementation may also improve aerobic exercise performance and increase gains in [[physical fitness|aerobic fitness]] when combined with [[high-intensity interval training]].<ref name="August 2017 supplementation review" /><ref name="Pimentel 2017 systematic review on HMB" /> These effects of HMB are more pronounced in untrained individuals and athletes who perform high intensity resistance or aerobic exercise.<ref name="ISSN position stand 2013" /><ref name="August 2017 supplementation review" /><ref name="Pimentel 2017 systematic review on HMB" /> In resistance-trained populations, the effects of HMB on muscle strength and lean body mass are limited.<ref name="Resistance-trained athletes meta-analysis">{{cite journal | vauthors = Sanchez-Martinez J, Santos-Lozano A, Garcia-Hermoso A, Sadarangani KP, Cristi-Montero C | title = Effects of beta-hydroxy-beta-methylbutyrate supplementation on strength and body composition in trained and competitive athletes: A meta-analysis of randomized controlled trials | journal = Journal of Science and Medicine in Sport | volume = 21 | issue = 7 | pages = 727–735 | date = July 2018 | pmid = 29249685 | doi = 10.1016/j.jsams.2017.11.003 | s2cid = 25776302 }}</ref> HMB affects muscle size, strength, mass, power, and recovery in part by stimulating [[myofibrillar]] muscle [[protein synthesis]] and inhibiting muscle [[protein breakdown]] through various mechanisms, including the activation of [[mechanistic target of rapamycin complex 1]] (mTORC1) and inhibition of [[proteasome]]-mediated [[proteolysis]] in skeletal muscles.<ref name="Pimentel 2017 systematic review on HMB">{{cite journal | vauthors = Silva VR, Belozo FL, Micheletti TO, Conrado M, Stout JR, Pimentel GD, Gonzalez AM | title = β-hydroxy-β-methylbutyrate free acid supplementation may improve recovery and muscle adaptations after resistance training: a systematic review | journal = Nutrition Research | volume = 45 | pages = 1–9 | date = September 2017 | pmid = 29037326 | doi = 10.1016/j.nutres.2017.07.008 | quote = 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].&nbsp;... Exogenous HMB-FA administration has shown to increase intramuscular anabolic signaling, stimulate muscle protein synthesis, and attenuate muscle protein breakdown in humans [2]. <!--Therefore, the anabolic and anti-catabolic properties of HMB-FA offer an appealing nutritional supplement for athletes participating in high-intensity, muscle damaging exercise.-->| url = https://repositorio.unesp.br/bitstream/11449/170023/1/2-s2.0-85027399749.pdf | hdl = 11449/170023 | hdl-access = free }}</ref><ref name="Pharmacology of HMB-FA in humans in vivo" />

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.<ref name="ISSN position stand 2013" /><ref name="Exercise-Induced Muscle Damage Meta-analysis" /> The greatest reduction in skeletal muscle damage from a single bout of exercise has been shown to occur when {{abbr|HMB-Ca|calcium β-hydroxy β-methylbutyrate monohydrate}} is ingested {{nowrap|1–2}}&nbsp;hours prior to exercise or {{abbr|HMB-FA|β-hydroxy β-methylbutyric acid}} is ingested {{nowrap|30–60}}&nbsp;minutes prior to exercise.<ref name="ISSN position stand 2013" />

In 2006, only about 2% of college [[student athlete]]s in the United States used HMB as a dietary supplement.<ref name="PEDs in sports 2015 review" /><ref name="NCAA 2006 study">{{cite web | author=The NCAA Research Staff | title=NCAA Study of Substance Use Habits of College Student-Athletes | url=https://www.ncaa.org/sites/default/files/14.%20Substance%20Use%20Report%202005.pdf | publisher=National Collegiate Athletic Association | access-date=24 June 2016 | page=7 | date=January 2006 | url-status=live | archive-url=https://web.archive.org/web/20160510001336/http://www.ncaa.org/sites/default/files/14.%20Substance%20Use%20Report%202005.pdf | archive-date=10 May 2016}}</ref> As of 2017, HMB has found widespread use as an [[ergogenic supplement]] among athletes.<ref name="HMB clinical evidence in sarcopenia 2017 review">{{cite journal | vauthors = Cruz-Jentoft AJ | title = Beta-hydroxy-beta-methyl butyrate (HMB): From experimental data to clinical evidence in sarcopenia | journal = Current Protein & Peptide Science | volume = 18| issue = 7| pages = 668–672| pmid = 28554316 | doi = 10.2174/1389203718666170529105026 | quote = HMB is widely used as an ergogenic supplement by young athletes.&nbsp;... This study shows that in healthy older adult, HMB supplementation may preserve muscle mass during 10&nbsp;days of bed rest. These results are encouraging, but need to be confirmed by other groups.| year = 2018 }}</ref> {{As of|2018|post=,}} HMB has not been banned by the [[National Collegiate Athletic Association]], [[World Anti-Doping Agency]], or any other prominent national or international athletic organization.<ref name="Lifestyle medicine WADA+NCAA">{{cite book | vauthors=Rippe JM | title=Lifestyle Medicine | date=March 2013 | publisher=CRC Press | isbn=978-1-4398-4544-8 | page=724 | edition=2nd | url=https://books.google.com/books?id=9ibOBQAAQBAJ&q=WADA+NCAA+HMB&pg=PA724 | section=Beta-Hydroxy beta-methylbutyrate | section-url=https://books.google.com/books?id=9ibOBQAAQBAJ&q=WADA+HMB&pg=PA724 | access-date=15 August 2016 | url-status=live | archive-url=https://web.archive.org/web/20180322000056/https://books.google.com/books?id=9ibOBQAAQBAJ&pg=PA724&lpg=PA724&dq=WADA+NCAA+HMB#v=onepage&q=WADA%20NCAA%20HMB | archive-date=22 March 2018}}</ref><ref name="WADA banned substances list">{{cite web | title=Prohibited List (January 2018) | publisher=World Anti-Doping Agency | url=https://www.wada-ama.org/sites/default/files/prohibited_list_2018_en.pdf | access-date=17 December 2017 | url-status=live | archive-url=https://web.archive.org/web/20171022032653/https://www.wada-ama.org/sites/default/files/prohibited_list_2018_en.pdf | archive-date=22 October 2017}}</ref><ref name="NCAA banned substances list">{{cite web | title=2018–19 NCAA Banned Drugs List | url=https://www.ncaa.org/2018-19-ncaa-banned-drugs-list | publisher=National Collegiate Athletic Association | access-date=22 August 2018 | date=10 June 2015 }}</ref>

==Side effects==
The [[drug safety|safety profile]] of HMB in adult humans is based upon evidence from [[clinical trials]] in humans and [[animal studies]].<ref name="Molecular Aspects of Medicine 2016 review" /><ref name="Efficacy and safety of leucine + HMB consumption">{{cite journal | vauthors = Borack MS, Volpi E | title = Efficacy and Safety of Leucine Supplementation in the Elderly | journal = The Journal of Nutrition | volume = 146 | issue = 12 | pages = 2625S–2629S | date = December 2016 | pmid = 27934654 | pmc = 5118760 | doi = 10.3945/jn.116.230771 | quote = 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 β-hydroxy-β-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&nbsp;mg ⋅ kg<sup>−1</sup> ⋅ d<sup>−1</sup> 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.&nbsp;... 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.}}</ref> In humans, no [[adverse effect]]s in young adults or older adults have been reported when HMB is taken in doses of 3&nbsp;grams per day for up to a year.<ref name="Molecular Aspects of Medicine 2016 review" /><ref name="Systematic review December 2013" /><ref name="Efficacy and safety of leucine + HMB consumption" /> Studies on young adults taking 6&nbsp;grams of HMB per day for up to 2&nbsp;months have also reported no adverse effects.<ref name="Systematic review December 2013" /><ref name="Efficacy and safety of leucine + HMB consumption" /> Studies with supplemental HMB on young, growing rats and livestock have reported no adverse effects based upon [[clinical chemistry]] or observable characteristics;<ref name="ISSN position stand 2013" /><ref name="HMB in animals 2015 review" /> for humans younger than 18, there is limited data on the safety of supplemental HMB.<ref name="ISSN position stand 2013" /> The [[human equivalent dose]] of HMB for the [[no-observed-adverse-effect level]] (NOAEL) that was identified in a rat model is approximately 0.4&nbsp;g/kg of [[Human body weight|body weight]] per day.{{#tag:ref|The NOAEL was established based upon a 3-month study involving several groups of [[Sprague-Dawley rat]]s that were administered different daily doses of {{abbr|HMB-FA|β-hydroxy β-methylbutyric acid}}.<ref name="Efficacy and safety of leucine + HMB consumption" /><ref name="HMB in animals 2015 review" /> No adverse effects were observed in any group that received HMB, so the highest daily dose of HMB that was administered in this study was identified as the NOAEL.<ref name="Efficacy and safety of leucine + HMB consumption" /><ref name="HMB in animals 2015 review" />|group="note"}}<ref name="Efficacy and safety of leucine + HMB consumption" /><ref name="HMB in animals 2015 review" />

Two animal studies have examined the effects of HMB supplementation in pregnant pigs on the offspring and reported no adverse effects on the fetus.<ref name="HMB in animals 2015 review" /> No clinical testing with supplemental HMB has been conducted on pregnant women,<ref name="MTI Pregnancy statement" /> and pregnant and lactating women are advised not to take HMB by [[Metabolic Technologies, Inc.]], the company that grants licenses to include HMB in dietary supplements, due to a lack of safety studies.<ref name="MTI Pregnancy statement">{{cite web|title=Who should not take HMB?|url=http://www.hmb.org/about-hmb/frequently-asked-questions/who-should-not-take-hmb/|publisher=Metabolic Technologies, Inc.|access-date=23 August 2016|quote=Pregnant or lactating women are advised against taking HMB because safety studies have not yet been conducted for these populations.|url-status=live|archive-url=https://web.archive.org/web/20160826061630/http://www.hmb.org/about-hmb/frequently-asked-questions/who-should-not-take-hmb/|archive-date=26 August 2016|date=11 September 2014}}</ref>

==Pharmacology==
<!--
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|image1 = Muscle protein synthesis signaling cascades.jpg
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|caption1 = Diagram of the [[anabolic]] biomolecular [[signaling cascade]]s that are involved in [[myofibrillar]] muscle protein synthesis and [[mitochondrial biogenesis]] in response to physical exercise and specific [[amino acid]]s or their derivatives (primarily [[leucine|{{nowrap|{{smallcaps all|L}}-leucine}}]] and HMB).<ref name="Skeletal muscle homeostasis 2016 review"/><br />{{hidden|Abbreviations and representations|{{bull}}PLD: [[phospholipase D]]<br />{{bull}}PA: [[phosphatidic acid]]<br />{{bull}}mTOR: [[mechanistic target of rapamycin]]<br />{{bull}}AMP: [[adenosine monophosphate]]<br />{{bull}}ATP: [[adenosine triphosphate]]<br />{{bull}}AMPK: [[AMP-activated protein kinase]]<br />{{bull}}PGC‐1α: [[PGC-1α|peroxisome proliferator-activated receptor gamma coactivator-1α]]<br />{{bull}}S6K1: [[p70S6 kinase]]<br />{{bull}}4EBP1: [[EIF4EBP1|eukaryotic translation initiation factor 4E-binding protein 1]]<br />{{bull}}eIF4E: [[eukaryotic translation initiation factor 4E]]<br />{{bull}}RPS6: [[ribosomal protein S6]]<br />{{bull}}eEF2: [[eukaryotic elongation factor 2]]<br />{{bull}}RE: [[resistance exercise]]; EE: [[endurance exercise]]<br />{{bull}}Myo: [[myofibrillar]]; Mito: [[mitochondria]]l<br />{{bull}}AA: [[amino acids]]<br />{{bull}}HMB: β-hydroxy β-methylbutyric acid<br />{{bull}}↑ represents activation<br />{{bull}}Τ represents inhibition | headerstyle=background:#ccccff | style=text-align:center;}}
}}

===Pharmacodynamics===
Several components of the [[signaling cascade]] that mediates the HMB-induced increase in human skeletal muscle protein synthesis have been identified ''[[in vivo]]''.<ref name="Pimentel 2017 systematic review on HMB" /><ref name="Pharmacology of HMB-FA in humans in vivo">{{cite journal | vauthors = 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 | title = Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism | journal = The Journal of Physiology | volume = 591 | issue = 11 | pages = 2911–2923 | date = June 2013 | pmid = 23551944 | pmc = 3690694 | doi = 10.1113/jphysiol.2013.253203 | quote = The stimulation of MPS through mTORc1-signalling following HMB exposure is in agreement with pre-clinical studies (Eley et al. 2008).&nbsp;... 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.&nbsp;...  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.&nbsp;... 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&nbsp;μU&nbsp;ml<sup>−1</sup>) while continuously infusing AAs (18&nbsp;g&nbsp;h<sup>−1</sup>) 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).}}</ref> Similar to HMB's [[Precursor (chemistry)|metabolic precursor]], {{nowrap|{{smallcaps all|L}}-leucine}}, HMB has been shown to increase protein synthesis in human skeletal muscle via [[phosphorylation]] of the [[mechanistic target of rapamycin]] (mTOR) and subsequent activation of {{abbrlink|mTORC1|mechanistic target of rapamycin complex 1}}, which leads to [[Translation (biology)|protein biosynthesis]] in cellular [[ribosome]]s via phosphorylation of mTORC1's immediate targets (i.e., the [[p70S6 kinase]] and the [[protein translation|translation]] repressor protein [[4EBP1]]).{{#tag:ref|Approximately equal doses of pure {{abbr|HMB-FA|β-hydroxy β-methylbutyric acid}} (2.42&nbsp;grams) and {{nowrap|{{smallcaps all|L}}-leucine}} (3.42&nbsp;grams) do not produce statistically distinguishable anabolic effects, as measured by the [[fractional synthesis]] of [[myofibril|myofibrillar proteins]], in the skeletal muscle of living humans.<ref name="Pharmacology of HMB-FA in humans in vivo" /><ref name="Sarcopenia July 2015 review" /> At 150&nbsp;minutes post-ingestion, these doses of HMB-FA and {{nowrap|{{smallcaps all|L}}-leucine}} increased muscle protein synthesis by ~70% and ~110% respectively in one study.<ref name="Pharmacology of HMB-FA in humans in vivo" /><ref name="Sarcopenia July 2015 review">{{cite journal | vauthors = Phillips SM | title = Nutritional supplements in support of resistance exercise to counter age-related sarcopenia | journal = Advances in Nutrition | volume = 6 | issue = 4 | pages = 452–460 | date = July 2015 | pmid = 26178029 | pmc = 4496741 | doi = 10.3945/an.115.008367 }}</ref>|group="note"}}<ref name="Pharmacology of HMB-FA in humans in vivo" /><ref name="Skeletal muscle homeostasis 2016 review">{{cite journal | vauthors = Brook MS, Wilkinson DJ, Phillips BE, Perez-Schindler J, Philp A, Smith K, Atherton PJ | title = Skeletal muscle homeostasis and plasticity in youth and ageing: impact of nutrition and exercise | journal = Acta Physiologica | volume = 216 | issue = 1 | pages = 15–41 | date = January 2016 | pmid = 26010896 | pmc = 4843955 | doi = 10.1111/apha.12532 | quote = 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). Although the mechanisms underlying the unique anabolic properties of leucine are incompletely defined, recent work in yeast and cultured mammalians cells has demonstrated that leucyl tRNA synthetase is upstream of activating the hitherto 'cellular AA sensor', the mechanistic target of rapamycin complex 1 (mTORC1) in response to leucine (Bonfils et al. 2012, Han et al. 2012). This was reaffirmed by experiments showing that of all the EAAs, leucine is the most effective EAA in increasing the activity (i.e. phosphorylation) of mTORC1 (Atherton et al. 2010b) and its substrates. }}</ref><ref name="Muscle atrophy-related signal transduction review">{{cite journal | vauthors = Dutt V, Gupta S, Dabur R, Injeti E, Mittal A | title = Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action | journal = Pharmacological Research | volume = 99 | pages = 86–100 | date = September 2015 | pmid = 26048279 | doi = 10.1016/j.phrs.2015.05.010 | quote = In an experimental animal model of cancer-induced cachexia, HMB treatment not only down-regulated the expression of key regulatory components of 19S and 20S proteasome–proteolytic pathway but also stimulated protein synthesis which further regulates the loss of muscle mass [40].&nbsp;... HMB is also involved in the regulation of satellite cell proliferation probably through reduction of nuclear apoptosis [46]. Overall, HMB treatments regulate skeletal muscle wasting by stimulating protein anabolic and inhibiting protein catabolic pathways (Fig. 3). }}</ref> Supplementation with HMB in several non-human animal species has been shown to increase the [[blood serum|serum]] concentration of [[growth hormone]] and [[insulin-like growth factor&nbsp;1]] (IGF-1) via an unknown mechanism, in turn promoting protein synthesis through increased mTOR phosphorylation.<ref name="ISSN position stand 2013" /><ref name="Molecular Aspects of Medicine 2016 review" /><ref name="HMB in animals 2015 review" /> Based upon limited clinical evidence in humans, supplemental HMB appears to increase the secretion of growth hormone and IGF-1 in response to resistance exercise.<ref name="Pimentel 2017 systematic review on HMB" />

{{As of|2016}}, the signaling cascade that mediates the HMB-induced reduction in muscle protein breakdown has not been identified in living humans, although it is well-established that it attenuates [[proteolysis]] in humans ''in vivo''.<ref name="Meta-analytic systematic review September 2015" /><ref name="Pharmacology of HMB-FA in humans in vivo" /> Unlike {{nowrap|{{smallcaps all|L}}-leucine}}, HMB attenuates muscle protein breakdown in an [[insulin]]-independent manner in humans.{{#tag:ref|At 150&nbsp;minutes post-ingestion, a 2.42&nbsp;gram dose of pure {{abbr|HMB-FA|β-hydroxy β-methylbutyric acid}} decreased skeletal muscle protein breakdown in living humans by 57% in one study.<ref name="Pharmacology of HMB-FA in humans in vivo" /><ref name="Sarcopenia July 2015 review" /> The effect of {{nowrap|{{smallcaps all|L}}-leucine}} on muscle protein breakdown is entirely dependent upon [[insulin]] secretion and consequently was not measured in the same study.<ref name="Pharmacology of HMB-FA in humans in vivo" /> By comparison, the insulin-dependent reduction in muscle protein breakdown following an entire meal that contains {{nowrap|{{smallcaps all|L}}-leucine}} and carbohydrates is ~50% on average.<ref name="Pharmacology of HMB-FA in humans in vivo" />|group="note"}}<ref name="Pharmacology of HMB-FA in humans in vivo"/> HMB is believed to reduce muscle protein breakdown in humans by inhibiting the [[19S]] and [[20S]] subunits of the [[ubiquitin–proteasome system]] in skeletal muscle and by inhibiting [[apoptosis]] of [[myonuclei|skeletal muscle nuclei]] via unidentified mechanisms.<ref name="Pharmacology of HMB-FA in humans in vivo"/><ref name="Molecular Aspects of Medicine 2016 review" /><ref name="Muscle atrophy-related signal transduction review" />

Based upon animal studies, HMB appears to be metabolized within skeletal muscle into [[cholesterol]], which may then be incorporated into the [[sarcolemma|muscle cell membrane]], thereby enhancing membrane integrity and function.<ref name="Elderly ICU weakness 2014 review" /><ref name="Effects of amino acid derivatives 2015 review" /> The effects of HMB on muscle [[protein metabolism]] may help stabilize muscle cell structure.<ref name="HMB in animals 2015 review"/> One review suggested that the observed HMB-induced reduction in the plasma concentration of muscle damage [[Biomarker (medicine)|biomarkers]] (i.e., muscle enzymes such as [[creatine kinase]] and [[lactate dehydrogenase]]) in humans following intense exercise may be due to a cholesterol-mediated improvement in muscle cell membrane function.<ref name="biomarkers" group="note" /><ref name="HMB in animals 2015 review" />

HMB has been shown to stimulate the [[cell proliferation|proliferation]], [[Cellular differentiation|differentiation]], and [[cell fusion|fusion]] of human [[myosatellite cells]] ''[[in vitro]]'', which potentially increases the regenerative capacity of skeletal muscle, by increasing the protein expression of certain [[myogenic regulatory factors]] (e.g., [[myoD]] and [[myogenin]]) and gene [[transcription factor]]s (e.g., [[MEF2]]).<ref name="ISSN position stand 2013" /><ref name="Systematic review December 2013" /><ref name="Human myosatellite cells in vitro" /> HMB-induced human myosatellite cell proliferation ''in vitro'' is mediated through the phosphorylation of the [[mitogen-activated protein kinase]]s [[ERK1]] and [[ERK2]].<ref name="Systematic review December 2013" /><ref name="HMB in animals 2015 review">{{cite journal | vauthors = Szcześniak KA, Ostaszewski P, Fuller JC, Ciecierska A, Sadkowski T | title = Dietary supplementation of β-hydroxy-β-methylbutyrate in animals – a review | journal = Journal of Animal Physiology and Animal Nutrition | volume = 99 | issue = 3 | pages = 405–417 | date = June 2015 | pmid = 25099672 | doi = 10.1111/jpn.12234 | quote = 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.&nbsp;... It is known that HMB supplementation decreases post-exercise levels of enzymes, indicating muscle damage, such as creatinine phosphokinase (CK) and lactate dehydrogenase (LDH), which suggests an enhancement of the muscle cell membrane function. This was shown in numerous studies in humans undergoing both resistance and endurance training (Wilson et al., 2013)&nbsp;... 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. The effect of HMB on protein metabolism may in fact help stabilize muscle structure more than any effect HMB may have on cholesterol metabolism in the cell. | doi-access = free }}</ref><ref name="Human myosatellite cells in vitro" /> HMB-induced human myosatellite differentiation and accelerated fusion of myosatellite cells into muscle tissue ''in vitro'' is mediated through the phosphorylation of [[protein kinase B|Akt]], a [[serine/threonine-specific protein kinase]].<ref name="Systematic review December 2013" /><ref name="HMB in animals 2015 review" /><ref name="Human myosatellite cells in vitro">{{cite journal | vauthors = Kornasio R, Riederer I, Butler-Browne G, Mouly V, Uni Z, Halevy O | title = Beta-hydroxy-beta-methylbutyrate (HMB) stimulates myogenic cell proliferation, differentiation and survival via the MAPK/ERK and PI3K/Akt pathways | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1793 | issue = 5 | pages = 755–763 | date = May 2009 | pmid = 19211028 | doi = 10.1016/j.bbamcr.2008.12.017 | department = primary source | quote = <!--Human myoblasts (satellite cells) were isolated as described previously&nbsp;...--> | doi-access =  }}</ref> <!-- HMB has also been shown to induce phosphorylation of ERK1, ERK2, and Akt, up-regulate MEF2 expression, and activate [[mTORC2|mechanistic target of rapamycin complex 2]] (mTORC2) in mouse [[neuro2a cell]]s ''in vitro''.<ref name="HMB-dependent Neuro2a neurite outgrowth">{{cite journal | vauthors = Salto R, Vílchez JD, Girón MD, Cabrera E, Campos N, Manzano M, Rueda R, López-Pedrosa JM | title = β-Hydroxy-β-Methylbutyrate (HMB) Promotes Neurite Outgrowth in Neuro2a Cells | journal = PLoS ONE | volume = 10 | issue = 8 | pages = e0135614 | date = August 2015 | pmid = 26267903 | pmc = 4534402 | doi = 10.1371/journal.pone.0135614 |doi-access=free | department = primary source | quote = 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.}}</ref>-->

===Pharmacokinetics===
[[File:ISSN HMB statement Fig 2.jpg|class=skin-invert-image|thumb|This graph shows the plasma concentration of HMB (in units of [[Mole (unit)|micromoles]] per liter of [[blood plasma]]) over time following ingestion of a 1&nbsp;gram dose of the calcium or free acid form of HMB.<ref name="ISSN position stand 2013" />|alt=Graphic of HMB plasma concentration over time]]

==== Comparison of pharmacokinetics between dosage forms ====
The free acid ({{abbr|HMB-FA|β-hydroxy β-methylbutyric acid}}) and monohydrated calcium salt ({{abbr|HMB-Ca|calcium β-hydroxy β-methylbutyrate monohydrate}}) forms of HMB have different [[pharmacokinetics]].<ref name="ISSN position stand 2013"/><ref name="HMB-FA commercial availability as of 2015" /> HMB-FA is more readily absorbed into the bloodstream and has a longer [[elimination half-life]] (3&nbsp;hours) relative to HMB-Ca (2.5&nbsp;hours).<ref name="ISSN position stand 2013"/><ref name="HMB-FA commercial availability as of 2015" /> Tissue uptake and utilization of HMB-FA is {{nowrap|25–40%}} higher than for HMB-Ca.<ref name="ISSN position stand 2013"/><ref name="HMB-FA commercial availability as of 2015"/> The fraction of an ingested dose that is excreted in urine does not differ between the two forms.<ref name="ISSN position stand 2013"/>

====Absorption of HMB-Ca====
After ingestion, {{abbr|HMB-Ca|calcium β-hydroxy β-methylbutyrate monohydrate}} is converted to {{nowrap|β-hydroxy β-methylbutyrate}} following [[Dissociation (chemistry)|dissociation]] of the calcium [[Moiety (chemistry)|moiety]] in the gut.<ref name="ISSN position stand 2013" /> When the HMB-Ca [[dosage form]] is ingested, the magnitude and time at which the peak plasma concentration of HMB occurs depends on the dose and concurrent food intake.<ref name="ISSN position stand 2013"/> Higher HMB-Ca doses increase the rate of [[Absorption (pharmacokinetics)|absorption]], resulting in a peak plasma HMB level ([[Cmax (pharmacology)|C<sub>max</sub>]]) that is disproportionately greater than expected of a linear [[dose-response relationship]] and which occurs sooner relative to lower doses.{{#tag:ref|In one study, ingestion of a 1&nbsp;gram dose of HMB-Ca by healthy volunteers produced a peak plasma HMB level of 120&nbsp;{{abbr|μM|micromolar}} at 2&nbsp;hours following ingestion, while ingestion of a 3&nbsp;gram dose of HMB-Ca produced a peak plasma HMB level of 487&nbsp;μM at 1&nbsp;hour following ingestion.<ref name="ISSN position stand 2013"/><br /> Consumption of 3&nbsp;grams of HMB-Ca with 75&nbsp;grams of [[glucose]] resulted in a lower peak plasma HMB level of 352&nbsp;μM which occurred later at 2&nbsp;hours following ingestion.<ref name="ISSN position stand 2013"/>|group="note"|name="Pharmacokinetics"}}<ref name="ISSN position stand 2013"/> Consumption of HMB-Ca with sugary substances slows the rate of HMB absorption, resulting in a lower peak plasma HMB level that occurs later.<ref name="Pharmacokinetics" group="note" /><ref name="ISSN position stand 2013"/>

====Excretion of HMB-Ca====
HMB is eliminated via the [[kidneys]], with roughly {{nowrap|10–40%}} of an ingested dose being excreted unchanged in urine.<ref name="ISSN position stand 2013"/><ref name="HMB athletic performance-related effects 2011 review" /> The remaining {{nowrap|60–90%}} of the dose is retained in tissues or excreted as HMB metabolites.<ref name="ISSN position stand 2013"/><ref name="HMB athletic performance-related effects 2011 review" /> The fraction of a given dose of HMB that is excreted unchanged in urine increases with the dose.{{#tag:ref|In one study, ingestion of a 1&nbsp;gram and 3&nbsp;gram HMB dose resulted in the excretion of 14% and 28% of the dose as HMB in urine, respectively.<ref name="ISSN position stand 2013"/>|group="note"}}<ref name="ISSN position stand 2013"/>

====Metabolism====
<noinclude>{{Leucine metabolism in humans|note=yes|note refs named=yes|align=right}} </noinclude>
The metabolism of HMB is catalyzed by an uncharacterized enzyme which converts it to [[β-hydroxy β-methylbutyryl-CoA|{{nowrap|β-hydroxy}} {{nowrap|β-methylbutyryl-CoA}}]] ({{nowrap|HMB-CoA}}).<ref name="HMB-CoA ⇔ HMB"/><ref name="Leucine metabolism" /> HMB-CoA is metabolized by either [[enoyl-CoA hydratase]] or another uncharacterized enzyme, producing [[β-methylcrotonyl-CoA]] ({{nowrap|MC-CoA}}) or [[hydroxymethylglutaryl-CoA]] ({{nowrap|HMG-CoA}}) respectively.<ref name="HMB athletic performance-related effects 2011 review" /><ref name="Leucine metabolism" /> {{nowrap|MC-CoA}} is then converted by the enzyme [[methylcrotonyl-CoA carboxylase]] to [[methylglutaconyl-CoA]] ({{nowrap|MG-CoA}}), which is subsequently converted to {{nowrap|HMG-CoA}} by [[methylglutaconyl-CoA hydratase]].<ref name="HMB athletic performance-related effects 2011 review" /><ref name="Leucine metabolism" /><ref name="BRENDA leucine metabolism">{{cite web|title=Leucine metabolism|url=http://www.brenda-enzymes.org/pathways/Maps/pathways/leucine_metabolism.svg|website=BRENDA|publisher=Technische Universität Braunschweig|access-date=12 August 2016|url-status=dead|archive-url=https://web.archive.org/web/20160817213425/http://www.brenda-enzymes.org/pathways/Maps/pathways/leucine_metabolism.svg|archive-date=17 August 2016}}</ref> {{nowrap|HMG-CoA}} is then cleaved into {{nowrap|[[acetyl-CoA]]}} and [[acetoacetate]] by [[HMG-CoA lyase|{{nowrap|HMG-CoA}} lyase]] or used in the production of cholesterol via the [[mevalonate pathway]].<ref name="HMB athletic performance-related effects 2011 review" /><ref name="Leucine metabolism" />

===Biosynthesis===
<noinclude>
HMB is synthesized in the human body through the [[metabolism]] of [[leucine|{{nowrap|{{smallcaps all|L}}-leucine}}]], a [[branched-chain amino acid]].<ref name="Leucine metabolism" /> </noinclude>In healthy individuals, approximately&nbsp;60% of dietary {{nowrap|{{smallcaps all|L}}-leucine}} is metabolized after several hours, with roughly 5% ({{nowrap|2–10%}}&nbsp;range) of dietary {{nowrap|{{smallcaps all|L}}-leucine}} being converted to {{if pagename|Leucine=[[β-hydroxy β-methylbutyric acid]] (HMB)|other=HMB}}.<ref name="HMB athletic performance-related effects 2011 review" /><ref name="Molecular Aspects of Medicine 2016 review">{{cite journal|vauthors=Brioche T, Pagano AF, Py G, Chopard A|date=August 2016|title=Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention|url=https://hal.archives-ouvertes.fr/hal-01837630/file/2016_Brioche_MAM_1.pdf|journal=Molecular Aspects of Medicine|volume=50|pages=56–87|doi=10.1016/j.mam.2016.04.006|pmid=27106402|s2cid=29717535 |quote=<!--HMB can decrease apoptosis, judging by a dramatic decrease in the number of TUNEL-positive nuclei in the soleus and plantaris of hindlimb-unloaded old rats treated with HMB, as compared to a placebo group.&nbsp;... Similar data were obtained in muscle cell cultures (Kornasio et al., 2009).&nbsp;...--> 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 inexpensive (~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.&nbsp;... 3&nbsp;g of CaHMB taken three times a day (1&nbsp;g each time) is the optimal posology, which allows for continual bioavailability of HMB in the body (Wilson et al., 2013)}}</ref><ref name="Leucine metabolism" /><includeonly> Around&nbsp;40% of dietary {{nowrap|{{smallcaps all|L}}-leucine}} is converted to {{nowrap|acetyl-CoA}}, which is subsequently used in the synthesis of other compounds.<ref name="Leucine metabolism" /></includeonly>

The vast majority of {{nowrap|{{smallcaps all|L}}-leucine}} metabolism is initially catalyzed by the [[branched-chain amino acid aminotransferase]] enzyme, producing {{nowrap|[[α-ketoisocaproate]]}} (α-KIC).<ref name="HMB athletic performance-related effects 2011 review">{{cite journal | vauthors = Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH | title = HMB supplementation: clinical and athletic performance-related effects and mechanisms of action | journal = Amino Acids | volume = 40 | issue = 4 | pages = 1015–1025 | date = April 2011 | pmid = 20607321 | doi = 10.1007/s00726-010-0678-0 | s2cid = 11120110 | url = https://repositorio.unal.edu.co/handle/unal/77957 | quote = 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 [α-KIC] that occurs mainly extrahepatically (Block and Buse 1990). Following this enzymatic reaction, [α-KIC] may follow one of two pathways. In the first, HMB is produced from [α-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 β-hydroxy-β-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).<!--<br /><br /> In the second pathway, after transamination, [α-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.--> }}</ref><ref name="Leucine metabolism">{{cite book | vauthors=Kohlmeier M | title=Nutrient Metabolism: Structures, Functions, and Genes | date=May 2015 | publisher=Academic Press | isbn=978-0-12-387784-0 | pages=385–388 | edition=2nd | section-url=https://books.google.com/books?id=aTQTAAAAQBAJ&q=beta-hydroxy%20beta-methylbutyrate%20HMB&pg=PA387 | url=https://books.google.com/books?id=aTQTAAAAQBAJ | access-date=6 June 2016 | section=Leucine | quote=Energy fuel: Eventually, most Leu is broken down, providing about 6.0kcal/g. About 60% of ingested Leu is oxidized within a few hours&nbsp;... Ketogenesis: A significant proportion (40% of an ingested dose) is converted into acetyl-CoA and thereby contributes to the synthesis of ketones, steroids, fatty acids, and other compounds | url-status=live | archive-url=https://web.archive.org/web/20180322000056/https://books.google.com/books?id=aTQTAAAAQBAJ&printsec=frontcover | archive-date=22 March 2018}}<br />[https://books.google.com/books?id=aTQTAAAAQBAJ&pg=PA386 Figure 8.57: Metabolism of {{smallcaps all|L}}-leucine] {{webarchive|url=https://web.archive.org/web/20180322000056/https://books.google.com/books?id=aTQTAAAAQBAJ&pg=PA386 |date=22 March 2018 }}</ref> α-KIC is mostly metabolized by the [[mitochondria]]l enzyme [[branched-chain alpha-keto acid dehydrogenase|branched-chain {{nowrap|α-ketoacid}} dehydrogenase]], which converts it to [[isovaleryl-CoA]].<ref name="HMB athletic performance-related effects 2011 review" /><ref name="Leucine metabolism"/> Isovaleryl-CoA is subsequently metabolized by [[isovaleryl-CoA dehydrogenase]] and converted to {{nowrap|MC-CoA}}, which is used in the synthesis of acetyl-CoA and other compounds.<ref name="Leucine metabolism" /> During [[biotin deficiency]], HMB can be synthesized from {{nowrap|MC-CoA}} via [[enoyl-CoA hydratase]] and an unknown [[thioesterase]] enzyme,<ref name="HMB-CoA ⇔ HMB">{{cite web|title=KEGG Reaction: R10759|url=http://www.genome.jp/dbget-bin/www_bget?rn:R10759|website=Kyoto Encyclopedia of Genes and Genomes|publisher=Kanehisa Laboratories|access-date=24 June 2016|url-status=live|archive-url=https://web.archive.org/web/20160701140720/http://www.genome.jp/dbget-bin/www_bget?rn:R10759|archive-date=1 July 2016}}</ref><ref name="pmid21918059" /><ref name="HMB-CoA ⇔ MC-CoA">{{cite web|title=KEGG Reaction: R04137|url=http://www.genome.jp/dbget-bin/www_bget?rn:R04137|website=Kyoto Encyclopedia of Genes and Genomes|publisher=Kanehisa Laboratories|access-date=24 June 2016|url-status=live|archive-url=https://web.archive.org/web/20160701144143/http://www.genome.jp/dbget-bin/www_bget?rn:R04137|archive-date=1 July 2016}}</ref> which convert {{nowrap|MC-CoA}} into {{nowrap|HMB-CoA}} and {{nowrap|HMB-CoA}} into HMB respectively.<ref name="pmid21918059">{{cite journal | vauthors = Mock DM, Stratton SL, Horvath TD, Bogusiewicz A, Matthews NI, Henrich CL, Dawson AM, Spencer HJ, Owen SN, Boysen G, Moran JH | title = Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans | journal = The Journal of Nutrition | volume = 141 | issue = 11 | pages = 1925–1930 | date = November 2011 | pmid = 21918059 | pmc = 3192457 | doi = 10.3945/jn.111.146126 | department = primary source | quote = 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.}}</ref> A relatively small amount of α-KIC is metabolized in the [[liver]] by the [[cytosol]]ic enzyme [[4-hydroxyphenylpyruvate dioxygenase]] (KIC dioxygenase), which converts α-KIC to HMB.<ref name="HMB athletic performance-related effects 2011 review" /><ref name="Leucine metabolism" /><ref name="KIC dioxygenase">{{cite web|title=Homo sapiens: 4-hydroxyphenylpyruvate dioxygenase reaction|url=http://www.biocyc.org/META/NEW-IMAGE?type=REACTION&object=RXN-13640|website=MetaCyc|publisher=SRI International|access-date=6 June 2016|date=20 August 2012}}</ref> In healthy individuals, this minor pathway&nbsp;– which involves the conversion of {{nowrap|{{smallcaps all|L}}-leucine}} to α-KIC and then HMB&nbsp;– is the predominant route of HMB synthesis.<ref name="HMB athletic performance-related effects 2011 review" /><ref name="Leucine metabolism" /><noinclude>{{clear right}}</noinclude>

==Chemistry==
<div class="skin-invert-image">
{{multiple image
<!--Layout parameters-->
|align = right
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<!--Image 1-->
|image1 = Butyric acid carbons 2.svg
|width1 = 235
|alt1 = Skeletal formula of butyric acid with the alpha, beta, and gamma carbons marked
|caption1 = [[Skeletal formula]] of [[butyric acid]] with the alpha, beta, and gamma carbons marked
<!--Image 2-->
|image2 = Beta-Hydroxy beta-methylbutyric acid 2.svg
|width2 = 235
|alt2 = Skeletal formula of β-hydroxy β-methylbutyric acid
|caption2 = Formula of {{nowrap|β-hydroxy β-methylbutyric acid}}
}}
</div>
{{nowrap|β-Hydroxy}} {{nowrap|β-methylbutyric}} acid is a [[carboxylic acid|monocarboxylic]] [[β-hydroxy acid]] and [[natural product]] with the [[molecular formula]] {{Chem2|C5H10O3|auto=yes}}.<ref name="HMDB" /><ref name="3-Hydroxyisovalerate ChEBI entry">{{cite web|title = 3-hydroxyisovalerate|url = https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:82957|website = Chemical Entities of Biological Interest|publisher = European Bioinformatics Institute|access-date = 20 August 2016|date = 16 September 2014|url-status = live|archive-date = 1 December 2017|archive-url = https://web.archive.org/web/20171201032101/https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:82957}}</ref> At room temperature, pure {{nowrap|β-hydroxy}} {{nowrap|β-methylbutyric}} acid occurs as a transparent, colorless to light yellow liquid which is soluble in water.<ref name="ChemSpider" /><ref name="Patent #WO2015094925 A1">{{cite patent| country = WO| number = 2015094925| status = application| title = Stable liquid filled hard capsule comprising beta-hydroxy-beta-methylbutyric acid | pubdate = 25 June 2015 | fdate = 11 December 2014 | pridate = 18 December 2013| inventor = White TO| assign1 = Capsugel Belgium Nv}}</ref> {{nowrap|β-Hydroxy}} {{nowrap|β-methylbutyric}} acid is a [[weak acid]] with a [[pKa|p''K''<sub>a</sub>]] of 4.4.<ref name = "Coffman_1958"/> Its [[refractive index]] (<math>\mathit{n}_\text{25°C}^\mathrm{\lambda=589nm}</math>) is 1.42.<ref name = "Coffman_1958"/>

===Chemical structure===
{{nowrap|β-Hydroxy}} {{nowrap|β-methylbutyric}} acid is a member of the [[carboxylic acid]] family of [[organic compounds]].<ref name="HMDB" /> It is a [[structural analog]] of [[butyric acid]] with a [[hydroxy group|hydroxyl]] [[functional group]] and a [[methyl group|methyl]] [[substituent]] located on its [[Alpha and beta carbon|beta carbon]].<ref name="HMDB" /><ref name="3-Hydroxyisovaleric acid ChEBI entry">{{cite web|title = 3-hydroxyisovaleric acid|url = https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:37084|website = Chemical Entities of Biological Interest|publisher = European Bioinformatics Institute|access-date = 20 August 2016|date = 23 October 2015|url-status = live|archive-date = 12 March 2016|archive-url = https://web.archive.org/web/20160312153637/http://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:37084}}</ref> By extension, other structural analogs include [[β-hydroxybutyric acid|{{nowrap|β-hydroxybutyric}} acid]] and [[β-methylbutyric acid|{{nowrap|β-methylbutyric}} acid]].<ref name="HMDB" /><ref name="3-Hydroxyisovaleric acid ChEBI entry" />

===Synthesis===
A variety of synthetic routes to {{nowrap|β-hydroxy}} {{nowrap|β-methylbutyric}} acid have been developed. The first reported [[chemical syntheses]] approached HMB by oxidation of [[alkene]], [[vicinal (chemistry)|vicinal]] [[diol]], and [[Alcohol (chemistry)|alcohol]] precursors:
* in 1877, Russian chemists Michael and [[Alexander Mikhaylovich Zaytsev|Alexander Zaytsev]] reported the preparation of HMB by oxidation of 2-methylpent-4-en-2-ol with [[chromic acid]] (H<sub>2</sub>CrO<sub>4</sub>);<ref name="First synthesis">The earliest citation for the synthesis of β-hydroxy β-methylbutyric acid in the [[Reaxys]] chemical database as of September 2016 is:<br />{{cite journal | vauthors = Saytzeff M, Saytzeff A | author-link2 = Alexander Mikhaylovich Zaytsev | title = Synthese des Allyldimethylcarbinols | trans-title = Synthesis of allyldimethylcarbinols| language = de | journal = Justus Liebig's Annalen der Chemie | date = 1877 | volume = 185 | issue = 2–3 | pages = 151–169 | doi = 10.1002/jlac.18771850204 | url = https://zenodo.org/record/1447335 }}</ref>
* in 1880 and 1889, Schirokoff and Reformatsky (respectively) reported that the oxidative cleavage of the vicinal diol 4-methylpentane-1,2,4-triol with acidified [[potassium permanganate]] (KMnO<sub>4</sub>) yields HMB<ref>{{cite journal | vauthors = Schirokoff A | title = Ueber die β-Dipropyl- und β-Diäthyläthylenmilchsäure und über die Oxydation des Allyldimethylcarbinols und Diallylcarbinols mit übermangansaurem Kalium | trans-title = On the β-dipropyl- and β-diethylenyl-lactic acid, and on the oxidation of the allyl dimethylcarbinol and diallylcarbinol with excess potassium | language = de | journal = Journal für Praktische Chemie | date = January 1881 | volume = 23 | issue = 1 | pages = 196–208 | doi = 10.1002/prac.18810230115 | url = https://zenodo.org/record/1427888 }}</ref><ref>{{cite journal | vauthors = Reformatzky B | title = Synthese einiger Glycerine mittelst unterchloriger Säure | trans-title = Synthesis of some glycerol by hypochlorous acid | language = de | journal = Journal für Praktische Chemie | date = 30 October 1889 | volume = 40 | issue = 1 | pages = 396–419 | doi = 10.1002/prac.18890400137| url = https://zenodo.org/record/1427948 }}</ref> – this result is closest related to the first synthesis as cold dilute KMnO<sub>4</sub> oxidises alkenes to vicinal ''cis''-diols which hot acid KMnO<sub>4</sub> further oxidises to carbonyl-containing compounds, and the diol intermediate is not obtained when hot acidic conditions are used for [[alkene oxidation]].<ref>{{cite book|title = Fundamentals of Organic Chemistry|edition = 7th| vauthors = McMurry JE |author-link = John E. McMurry|pages = 124–126, 142|chapter = Oxidation of Alkenes: Epoxidation, Hydroxylation, and Cleavage|isbn = 978-1-4390-4971-6 |publisher = [[Cengage Learning]]|year = 2010|chapter-url = https://books.google.com/books?id=3_4oLh-OWEcC&q=oxidation+alkene+KMnO4&pg=PA142}}</ref>  In other words, [[racemic]] 4-methylpentane-1,2,4-triol is a [[derivative (chemistry)|derivative]] of 2-methylpent-4-en-2-ol and β-hydroxy β-methylbutyric acid is a derivative of both; and,
* in 1892, Kondakow reported the preparation of HMB by permanganate oxidation of 3-methylbutane-1,3-diol.<ref>{{cite journal | vauthors = Kondakow J | title = On the action of mineral acids on dimethylallyls <!-- Surely this is a trans-title... what was the title? --> | date= 1892 | language = ru | journal = Zhurnal Russkago Fiziko-Khimicheskago Obshchestva (Journal of the Russian Physico-Chemical Society) | volume = 1 <!-- Is this volume correct?  Volume 1 of the journal was in 1869, volume 38 was in 1906, so shouldn't 1892 be volume 24?  From 1907, the journal split into A / B sections for physics and chemistry, both starting at volume 39 --> | pages = 508–513 }} abstracted by {{cite journal | vauthors = Grosset | title = Ueber die Einwirkung von Mineralsauren auk Dimethylallen | language = de | trans-title = On the action of mineral acids on dimethylallyls | journal = Berichte der Deutschen Chemischen Gesellschaft | date = 1893 | volume = 26 | issue = 4| page = 96 | doi = 10.1002/cber.18930260412 }}</ref>
[[File:HMB synthesis historical.svg|class=skin-invert-image|600px|center|thumb|alt=Graphic of the first synthetic routes to β-hydroxy β-methylbutyric acid|First synthetic routes to {{nowrap|β-hydroxy}} {{nowrap|β-methylbutyric}} acid]]

Depending on the experimental conditions, [[cycloaddition]] of [[acetone]] and [[ketene]] produces either {{nowrap|β-isovalerolactone}} or 4,4-dimethyloxetan-2-one,<ref>{{cite journal | vauthors = Gresham TL, Jansen JE, Shaver FW, Beears WL | title = β-Propiolactone. XIV. β-Isovalerolactone | journal = Journal of the American Chemical Society | date = January 1954 | volume = 76 | issue = 2 | pages = 486–488 | doi = 10.1021/ja01631a045 }}</ref><ref>{{cite patent | country = WO | number = 2012140276 | status = application | title = Process for the preparation of 3-hydroxy-3-methylbutyric acid or its calcium salts | pubdate = 10 January 2013 | gdate = | fdate = 19 August 2012 | pridate = 17 November 2011 | inventor = Noti C, Schmid L, Rittiner B, Hanselmann P, Bierstedt A | assign1 = Lonza Ltd | url = }}</ref> both of which [[Hydrolysis|hydrolyze]] under basic conditions to yield the conjugate base of HMB. The [[haloform reaction]] provides another pathway to HMB involving the exhaustive halogenation of the methyl-ketone region of [[diacetone alcohol]] with [[sodium hypobromite]] or [[sodium hypochlorite]];<ref name = "Coffman_1958">{{cite journal | vauthors = Coffman DD, Cramer R, Mochel WE | title = Syntheses by Free-radical Reactions. V. A New Synthesis of Carboxylic Acids | journal = Journal of the American Chemical Society | date = June 1958 | volume = 80 | issue = 11 | pages = 2882–2887 | doi = 10.1021/ja01544a072 }}</ref><ref name = DiacetoneAlcohol>{{cite journal | vauthors = Kohn M | title = Zur Kenntnis des Diacetonalkohols und des Mesityloxyds | trans-title = Knowledge of diacetone alkohols and mesityl oxide | journal = Monatshefte für Chemie und Verwandte Teile Anderer Wissenschaften | date = September 1903 | volume = 24 | issue = 9 | pages = 765–772 | doi = 10.1007/BF01526057 | s2cid = 96317019 }}</ref><ref>{{cite book | vauthors = Doraiswamy LK | title = Organic Synthesis Engineering | date = February 2001 | publisher = Oxford University Press | location = New York | isbn = 978-0-19-509689-7 | chapter-url = https://books.google.com/books?id=_0rnCwAAQBAJ&pg=PA103 | pages = 102–124 | chapter = Example 5.2 }}</ref> Diacetone alcohol is readily available from the [[aldol condensation]] of acetone.<ref name = DiacetoneAlcohol /> An [[organometallic chemistry|organometallic]] approach to HMB involves the [[carboxylation]] of [[tert-butyl alcohol|''tert''-butyl alcohol]] with [[carbon monoxide]] and [[Fenton's reagent]] ([[hydrogen peroxide]] and [[ferrous iron]]).<ref name = "Coffman_1958"/><ref name="Kochi">{{cite book | vauthors = Kochi JK | title = Organometallic Mechanisms and Catalysis: The Role of Reactive Intermediates in Organic Processes | date = December 2012 | publisher = Elsevier | location = New York | isbn = 978-0-323-14410-0 | page = 67 | chapter = Homolytic Mechanism in Metal Catalysis | chapter-url = https://books.google.com/books?id=xYT2UQYyb3IC&pg=PA67 | url-status = live | archive-url = https://web.archive.org/web/20180322000056/https://books.google.com/books?id=xYT2UQYyb3IC&pg=PA67 | archive-date = 22 March 2018}}</ref> Alternatively, HMB can be prepared through [[fermentation|microbial oxidation]] of {{nowrap|β-methylbutyric}} acid by the fungus ''[[Galactomyces reessii]]''.<ref name="pmid9361403">{{cite journal | vauthors = Lee IY, Nissen SL, Rosazza JP | title = Conversion of beta-methylbutyric acid to beta-hydroxy-beta-methylbutyric acid by ''Galactomyces reessii'' | journal = Applied and Environmental Microbiology | volume = 63 | issue = 11 | pages = 4191–4195 | date = November 1997 | pmid = 9361403 | pmc = 168736 | doi = 10.1128/AEM.63.11.4191-4195.1997| bibcode = 1997ApEnM..63.4191L | department = primary source }}</ref>
[[File:HMB synthesis 2.svg|class=skin-invert-image|700px|center|thumb|alt=Graphic of the later synthetic routes to β-hydroxy β-methylbutyric acid|Later synthetic routes to {{nowrap|β-hydroxy}} {{nowrap|β-methylbutyric}} acid]]

===Detection in body fluids===
{{clear right}}
{| class="wikitable sortable" style="text-align:center; margin-left:8px; float:right;"
|+ HMB concentrations measured in healthy individuals
! scope="col" class="sortable"   rowspan="2" | [[Biofluid]]
! scope="col" class="unsortable" rowspan="2" | Age group
! scope="col" class="sortable"   colspan="3" | Concentration
! scope="col" class="unsortable" rowspan="2" | <small>Sources</small>
|-
! scope="col" class="sortable"   | Mean
! scope="col" class="unsortable" | Range
! scope="col" class="sortable"   | Units
|-
| [[Blood plasma]] || Adults (18+) || 4.0 || 0–10.0 || {{abbr|μM|micromolar}} || <ref name="HMDB" />
|-
| {{abbrlink|CSF|cerebrospinal fluid}} || Adults (18+) || 4.0 || 2.0–6.0 || μM || <ref name="HMDB" />
|-
| [[Sarcoplasma]] || Adults (21–23) || 7.0 || 4.0–10.0 || μM <!--reported in units of μmol/L--> || <ref name="Pharmacology of HMB-FA in humans in vivo" />
|-
| Breast milk || Adults (18+) || – || 42–164 || {{abbr|μg/L|micrograms per liter}} || <ref name="Human milk LC–MS" />
|-
| Urine || Adults (18+) || – || 3.2–25.0 || {{abbr|μmol/mmol|micromoles per millimole}}&nbsp;creatinine || <ref name="HMDB" />
|-
| Urine || Children (1–18) || – || 0–68 || μmol/mmol&nbsp;creatinine || <ref name="HMDB" />
|}
The concentration of naturally produced HMB has been measured in several human [[body fluid]]s using [[nuclear magnetic resonance spectroscopy]], [[liquid chromatography–mass spectrometry]], and [[gas chromatography–mass spectrometry]] methods.<ref name="Human milk LC–MS">{{cite journal | vauthors = Ehling S, Reddy TM | title = Direct Analysis of Leucine and Its Metabolites β-Hydroxy-β-methylbutyric Acid, α-Ketoisocaproic Acid, and α-Hydroxyisocaproic Acid in Human Breast Milk by Liquid Chromatography-Mass Spectrometry | journal = Journal of Agricultural and Food Chemistry | volume = 63 | issue = 34 | pages = 7567–7573 | date = September 2015 | pmid = 26271627 | doi = 10.1021/acs.jafc.5b02563 | department = primary source }}</ref><ref name="HMDB">{{cite HMDB | title=Showing metabocard for 3-Hydroxyisovaleric acid (HMDB0000754)|author1-link=David S. Wishart | url=http://www.hmdb.ca/metabolites/HMDB00754}}</ref> In the blood plasma and [[cerebrospinal fluid]] (CSF) of healthy adults, the average [[molar concentration]] of HMB has been measured at 4.0&nbsp;[[micromolar]] (μM).<ref name="HMDB" /> The average concentration of HMB in the [[sarcoplasma|intramuscular fluid]] of healthy men of ages {{nowrap|21–23}} has been measured at 7.0&nbsp;μM.<ref name="Pharmacology of HMB-FA in humans in vivo" /> In the urine of healthy individuals of any age, the excreted urinary concentration of HMB has been measured in a range of {{nowrap|0–68}}&nbsp;[[micromole]]s per millimole (μmol/mmol) of [[creatinine]].<ref name="HMDB" /> In the breast milk of healthy lactating women, HMB and {{nowrap|{{smallcaps all|L}}-leucine}} have been measured in ranges of {{nowrap|42–164}}&nbsp;μg/L and {{nowrap|2.1–88.5}}&nbsp;mg/L.<ref name="Human milk LC–MS" /> In comparison, HMB has been detected and measured in the milk of healthy cows at a concentration of {{nowrap|<20–29}}&nbsp;μg/L.<ref name="Bovine milk LC–MS">{{cite journal | vauthors = Ehling S, Reddy TM | title = 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 | journal = Journal of Agricultural and Food Chemistry | volume = 62 | issue = 7 | pages = 1506–1511 | date = February 2014 | pmid = 24495238 | doi = 10.1021/jf500026s | department = primary source }}</ref> This concentration is far too low to be an adequate dietary source of HMB for obtaining pharmacologically active concentrations of the compound in blood plasma.<ref name="Bovine milk LC–MS" />

In a study where participants consumed 2.42&nbsp;grams of pure {{abbr|HMB-FA|β-hydroxy β-methylbutyric acid}} while fasting, the average plasma HMB concentration increased from a basal level of 5.1&nbsp;{{abbr|μM|micromolar}} to 408&nbsp;μM after 30&nbsp;minutes.<ref name="Pharmacology of HMB-FA in humans in vivo" /> At 150&nbsp;minutes post-ingestion, the average plasma HMB concentration among participants was 275&nbsp;μM.<ref name="Pharmacology of HMB-FA in humans in vivo" />

Abnormal HMB concentrations in urine and blood plasma have been noted in several disease states where it may serve as a [[diagnostic biomarker]], particularly in the case of [[metabolic disorder]]s.<ref name="HMDB" /> The following table lists some of these disorders along with the associated HMB concentrations detected in urine or blood plasma.<ref name="HMDB" />
{| class="wikitable sortable" style="text-align:center;"
|+ Abnormal HMB concentrations measured in disease states
! scope="col" class="sortable"   rowspan="2" | Medical condition
! scope="col" class="sortable"   rowspan="2" | Biofluid
! scope="col" class="unsortable" rowspan="2" | Age group
! scope="col" class="sortable"   colspan="3" | Concentration
! scope="col" class="unsortable" rowspan="2" | <small>Sources</small>
|-
! scope="col" class="sortable"    | Mean
! scope="col" class="unsortable"  | Range
! scope="col" class="sortable"    | Units
|-
| [[Biotinidase deficiency]]<sup>†</sup> || Blood || Adults (18+) || 9.5 || 0–19.0 || {{abbrlink|μM|micromolar}} || <ref name="HMDB" />
|-
| Biotinidase deficiency<sup>†</sup> || Blood || Children (1–13) || 88.0 || 10.0–166.0 || μM || <ref name="HMDB" />
|-
| Biotinidase deficiency<sup>†</sup> || Urine || Children (1–13) || 275.0 || 50.0–500.0 || {{abbr|μmol/mmol|micromoles per millimole}}&nbsp;[[creatinine]] || <ref name="HMDB" />
|-
| [[3-Methylglutaconic aciduria|3-Methylglutaconic aciduria (Type I)]]<sup>†</sup> || Urine || Children (1–13) || 200.0 || 150.0–250.0 || μmol/mmol&nbsp;creatinine || <ref name="HMDB" />
|-
| [[Eosinophilic esophagitis]] || Urine || Children (1–13) || 247.4 || 0–699.4 || μmol/mmol&nbsp;creatinine|| <ref name="HMDB" />
|-
| [[Gastroesophageal reflux disease]] || Urine || Children (1–13) || 119.8 || 5.5–234.0 || μmol/mmol&nbsp;creatinine || <ref name="HMDB" />
|-
| [[HMG-CoA lyase deficiency]]<sup>†</sup> || Urine || Children (1–13) || 2030.0 || 60.0–4000.0 || μmol/mmol&nbsp;creatinine || <ref name="HMDB" />
|-
| [[3-Methylcrotonylglycinuria|MC-CoA carboxylase deficiency]]<sup>†</sup> || Urine || Children (1–13) || 30350.0 || 1700.0–59000.0 || μmol/mmol&nbsp;creatinine || <ref name="HMDB" />
|-
! scope="col" colspan="7" style="text-align:center;" | <small>{{nobold|A <sup>†</sup> indicates that the medical condition is a [[metabolic disorder]].}}</small>
|}

==History==
The first reported [[chemical synthesis]] of HMB was published in 1877 by the Russian chemists Michael and [[Alexander Mikhaylovich Zaytsev|Alexander Zaytsev]].<ref name="First synthesis" /> HMB was isolated from the bark of ''[[Erythrophleum couminga]]'' (a Madagascan tree) in 1941 by [[Leopold Ružička]].<ref>{{cite journal | vauthors = Ružička L, Dalma G, Engel BG, Scott WE | author-link1 = Leopold Ružička | title = Zur Kenntnis der Erythrophleum-Alkaloide. (5. Mitteilung). Identifizierung der niedermolekularen Spaltsäure des Coumingins | trans-title = Concerning erythrophleum alkaloids. (5th Communication). Identification of the low molecular weight cleavage acids from coumingin | language = de | journal = Helvetica Chimica Acta | date = 1941 | volume = 24 | issue = 1| pages = 1449–1458 | doi = 10.1002/hlca.194102401171 }}</ref> The earliest reported isolation of HMB as a human [[metabolite]] was by Tanaka and coworkers in 1968 from a patient with [[isovaleric acidemia]].<ref name="pmid5656832">{{cite journal | vauthors = Tanaka K, Orr JC, Isselbacher KJ | title = Identification of beta-hydroxyisovaleric acid in the urine of a patient with isovaleric acidemia | journal = Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism | volume = 152 | issue = 3 | pages = 638–41 | date = May 1968 | pmid = 5656832 | doi = 10.1016/0005-2760(68)90107-0 | department = primary source }}</ref><ref>{{cite book | vauthors = Tanaka K | title = Biology of Brain Dysfunction | chapter = Disorders of Organic Acid Metabolism | veditors = Gaull GE | pages = 145–214 | date = 1975 | publisher = Springer US | location = Boston, MA | isbn = 978-1-4684-2675-5 | doi = 10.1007/978-1-4684-2673-1_3}}</ref>

The effects of HMB on human skeletal muscle were first discovered by Steven L. Nissen at [[Iowa State University]] in the {{nowrap|mid-1990s}}.<ref name="Iowa State University" /><ref name="Discovered">{{cite book | vauthors=Fitzgerald M | title=Diet Cults: The Surprising Fallacy at the Core of Nutrition Fads and a Guide to Healthy Eating for the Rest of Us | date=May 2014 | publisher=Pegasus Books | isbn=978-1-60598-595-4 | page=[https://archive.org/details/dietcultssurpris0000fitz/page/148 148] | url=https://archive.org/details/dietcultssurpris0000fitz | url-access=registration | access-date=31 July 2016 | quote=HMB was discovered in the mid-1990s by Steve Nissen, a researcher at Iowa State University }}</ref> Nissen founded a company called [[Metabolic Technologies, Inc.]] (MTI) around the time of his discovery, which later acquired six HMB-related [[patent]]s that the company has used to license the right to manufacture and incorporate HMB into dietary supplements.<ref name="Discovered" /><ref name="ISU FY11 proposal">{{cite web | title=The University of Iowa Economic Development Grow Iowa Values Fund Proposal: Fiscal Year 2011 | url=http://www.iowaregents.edu/media/cms/givffy11-pdf2DF5CFCB.pdf | publisher=University of Iowa | pages=13–16 | access-date=1 September 2016 | url-status=live | archive-url=https://web.archive.org/web/20160901165212/http://www.iowaregents.edu/media/cms/givffy11-pdf2DF5CFCB.pdf | archive-date=1 September 2016}}</ref><ref>{{cite web | url = https://patents.justia.com/assignee/metabolic-technologies-inc | title = Patents Assigned to Metabolic Technologies, Inc. | work = Justia Patent }}<br />{{As of|2018|03|post=,}} granted patents include: {{US patent|8815280|US8815280}}, {{US patent|9259430|US9259430}}, {{US patent|9539224|US9539224}}, {{US patent|9707241|US9707241}}, and  {{US patent|9770424|US9770424}}.</ref> When it first became available commercially in the late 1990s, HMB was marketed solely as an exercise supplement to help athletes and bodybuilders build muscle.<ref name="ISU FY11 proposal" /> MTI subsequently developed two HMB-containing products, Juven and Revigor, to which [[Abbott Nutrition]] obtained the market rights in 2003 and 2008 respectively.<ref name="Iowa State University" /><ref name="ISU FY11 proposal" /> Since then, Abbott has marketed Juven as a medical food and the Revigor brand of HMB as an active ingredient in food products (e.g., certain formulations of Ensure) and other medical foods (e.g., certain formulations of Juven).<ref name="Iowa State University" /><ref name="Abbott Nutrition product overview">{{cite web|title=Abbott Nutrition Overview|url=http://prod3.dam.abbott.com/en-us/documents/pdfs/media-center/nutrition-fact-sheet.pdf|website=Abbott|publisher=Abbott Laboratories|access-date=3 September 2016|url-status=dead|archive-url=https://web.archive.org/web/20160903081517/http://prod3.dam.abbott.com/en-us/documents/pdfs/media-center/nutrition-fact-sheet.pdf|archive-date=3 September 2016}}</ref><ref name="ISU FY11 proposal" />

== See also ==
* [[3-Aminoisobutyric acid]]

== Notes ==
{{Reflist|group="note"}}

== Reference notes ==
{{Reflist|group="sources"}}

== References ==
{{Reflist|refs=
<ref name="HMB athletic performance-related effects 2011 reviewb">{{cite journal | vauthors = Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH | title = HMB supplementation: clinical and athletic performance-related effects and mechanisms of action | journal = Amino Acids | volume = 40 | issue = 4 | pages = 1015–1025 | date = April 2011 | pmid = 20607321 | doi = 10.1007/s00726-010-0678-0 | s2cid = 11120110 | url = https://repositorio.unal.edu.co/handle/unal/77957 | quote = 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 [α-KIC] that occurs mainly extrahepatically (Block and Buse 1990). Following this enzymatic reaction, [α-KIC] may follow one of two pathways. In the first, HMB is produced from [α-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 β-hydroxy-β-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).<!--<br /><br /> In the second pathway, after transamination, [α-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.--> }}</ref>}}

== External links ==
{{Commons category|Beta-Hydroxy beta-methylbutyrate}}
* {{MeSH name|Beta-Hydroxyisovaleric acid}}

{{Amino acid metabolism intermediates|state=collapsed}}
{{Cholesterol and steroid intermediates}}
{{Dietary supplement}}
{{Mineral supplements}}

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