beta-Hydroxy beta-methylbutyric acid

β-Hydroxy β-methylbutyric acid

Top: β-Hydroxy β-methylbutyric acid Bottom: β-Hydroxy β-methylbutyrate
Clinical data
Routes of administration	By mouth or nasogastric[1]
ATC code	none
Legal status
Legal status	US: OTC UN: Unscheduled
Pharmacokinetic data
Metabolites	HMB-CoA, HMG-CoA, mevalonate, cholesterol, acetoacetyl-CoA, acetyl-CoA
Onset of action	HMB-FA: 30–60 minutes[2] HMB-Ca: 1–2 hours[2]
Biological half-life	HMB-FA: 3 hours[2] HMB-Ca: 2.5 hours[2]
Excretion	Renal (10–40% excreted)[2][3]
Identifiers
IUPAC name 3-hydroxy-3-methylbutanoic acid
Synonyms	Conjugate acid form: β-hydroxyisovaleric acid 3-hydroxyisovaleric acid Conjugate base form: hydroxymethylbutyrate
CAS Number	625-08-1
PubChem (CID)	69362
ChemSpider	62571
UNII	3F752311CD
ChEBI	CHEBI:37084
Chemical and physical data
Formula	C5H10O3
Molar mass	118.131 g/mol
3D model (Jmol)	Interactive image
Density	~1.1 g/cm^3 at 20 °C[4]
Melting point	−80 °C (−112 °F) (glass)[5]
Boiling point	128 °C (262 °F) at 7 mmHg[4][6]
SMILES CC(C)(CC(=O)O)O
InChI InChI=1S/C5H10O3/c1-5(2,8)3-4(6)7/h8H,3H2,1-2H3,(H,6,7) Key:AXFYFNCPONWUHW-UHFFFAOYSA-N
(verify)

β-Hydroxy β-methylbutyric acid^{[note 1]} (HMB), also known as β-hydroxy β-methylbutyrate, is a substance that is naturally produced in humans and used as nutritional supplement. It is added to certain medical foods to help provide nutritional support for people with muscle wasting due to cancer or HIV/AIDS and to promote wound healing.^[1][7][8] Supplemental HMB inhibits the loss of lean body mass in muscle wasting conditions, particularly in individuals with muscle lose with age or during bed rest. It is often used in addition to resistance exercise.^[9][10][11] Supplemental HMB is also used by athletes to increase exercise-induced gains in muscle size, muscle strength, and lean body mass, reduce exercise-induced skeletal muscle damage, and speed recovery from high-intensity exercise.^{[2][9][12][13]} HMB produces these effects in part by stimulating the production of proteins and inhibiting the breakdown of proteins in muscle tissue.^[9][14][15] Medical reviews have found no issues with safety from long-term use as a dietary supplement in adults.^{[2][9][12][16]}

HMB is a metabolite of L-leucine that is produced in the body through oxidation of the ketoacid of L-leucine (α-ketoisocaproic acid).^[2][17] Since only a small fraction of L-leucine is metabolized into HMB, pharmacologically active concentrations of the compound in blood and muscle can only be achieved by supplementing HMB directly.^[2][11][18] A healthy adult produces approximately 0.3 grams per day, while supplemental HMB is usually taken in doses of 3–6 grams per day.^[16] HMB is sold worldwide as a dietary supplement at a cost of about US$30–50 per month when taking 3 grams per day.^[9][12][19] HMB is also contained in several nutritional products, including certain formulations of Ensure, Juven, and Myoplex.^[7][20] Small amounts of HMB are present in certain foods, such as alfalfa, asparagus, avocados, cauliflower, grapefruit, catfish, and milk.^[21][22][23]

The effects of HMB on human skeletal muscle were first discovered by Steven L. Nissen at Iowa State University in the mid-1990s.^[7][24] As of 2015, HMB has not been banned by the National Collegiate Athletic Association (NCAA), World Anti-Doping Agency (WADA), or any other prominent national or international athletic organization.^[12][25][26] In 2006, about 1.9% of college student athletes in the United States used HMB as a dietary supplement and the use of HMB among these athletes appears to be increasing.^[12][27]

Uses

Available forms

HMB is sold worldwide as an over-the-counter dietary supplement in the free acid form, β-hydroxy β-methylbutyric acid (HMB-FA), and as a monohydrated calcium salt of the conjugate base, calcium β-hydroxy β-methylbutyrate monohydrate (HMB-Ca, CaHMB).^[19] It is sold at a cost of about US$30–50 per month when taken in doses of 3 grams per day.^[9][12] HMB is also contained in several nutritional products and medical foods marketed by Abbott Laboratories (e.g., certain formulations of Ensure, Juven, and Myoplex),^[7][20] and is present in insignificant quantities in certain foods, such as alfalfa, asparagus, avocados, cauliflower, grapefruit, catfish, and milk.^[21][22][23]

Medical

Some branded products that contain HMB (i.e., certain formulations of Ensure and Juven) are medical foods that are used medically for providing 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.^[1][7][8] Juven, a nutrition product which contains 3 grams of HMB-Ca, 14 grams of L-arginine, and 14 grams of L-glutamine per two servings,^[1] has been shown to improve lean body mass during clinical trials in individuals with AIDS and cancer, but not rheumatoid cachexia.^[16][28] Clinical trials with Juven for AIDS have also demonstrated improvements in immune status, as measured by a reduced HIV viral load relative to controls and higher CD3⁺ and CD8⁺ cell counts.^{[note 2][16][28]} The efficacy of Juven for the treatment of cancer cachexia was also examined in a phase 3 clinical trial which found a strong trend (i.e., p=.08) for an improvement in lean body mass relative to controls;^[16][30] however, according to the authors of the trial itself and a systematic review that included it, the trial did not adequately test the ability of Juven to prevent or reverse the loss of lean body mass in individuals with cancer cachexia since the majority of participants did not complete the study.^[16][30]

Supplemental HMB has been used in a number of clinical trials as a treatment for preserving lean body mass in muscle wasting conditions, particularly sarcopenia and during bed rest, and is often employed as an adjunct therapy in conjunction with resistance exercise.^{[9][10][11][14]} A growing body of evidence supports the efficacy of HMB in nutritional support for reducing, or even reversing, the loss of muscle mass, muscle function, and muscle strength that occurs in hypercatabolic disease states such as cancer cachexia;^[9][11][31] 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.^[9][11] Based upon a meta-analysis of seven randomized controlled trials that was published in 2015, HMB supplementation can preserve lean muscle mass in older adults.^{[note 3][10]} HMB does not appear to significantly affect fat mass in older adults.^[10] As of 2015, more research is needed to determine the precise effects on muscle strength and function in this age group.^[10]

Clinical trials that used HMB for the treatment of muscle wasting have involved the administration of 3 grams of HMB per day under different dosing regimens.^[9] According to one review, an optimal dosing regimen is to administer it in one 1 gram dose, three times a day, since this ensures elevated plasma concentrations of HMB throughout the day;^[9] however, as of June 2016 the best dosing regimen for each condition (i.e., bed rest, cachexia, sarcopenia, etc) is still being investigated.^[11]

Enhancing performance

When combined with an appropriate exercise program, dietary supplementation with HMB dose-dependently augments gains in muscle hypertrophy (i.e., the size of a muscle),^[2][10][12] muscle strength,^[9][12][13] and lean body mass,^[9][12][13] reduces exercise-induced skeletal muscle damage,^{[note 4][10][12][13]} and may expedite recovery from high-intensity exercise.^[2][12] HMB produces these effects in part by stimulating myofibrillar muscle protein synthesis and inhibiting muscle protein breakdown through various mechanisms, including activation of mechanistic target of rapamycin complex 1 (mTORC1) and inhibition of proteasome-mediated proteolysis in skeletal muscles.^[9][14][15]

A commercially available formulation of HMB. Each size 000 gelatin capsule contains 1 gram of HMB-Ca and an unspecified amount of microcrystalline cellulose and magnesium stearate.

The inhibition of exercise-induced skeletal muscle damage by HMB is affected by the time that it is used relative to exercise.^[2][12] The greatest reduction in skeletal muscle damage from a single bout of exercise has been shown to occur when HMB-Ca is ingested 1–2 hours prior to exercise or HMB-FA is ingested 30–60 minutes prior to exercise.^[2]

As of 2015, HMB has not been banned by the NCAA, WADA, or any other prominent national or international athletic organization.^[12][25][26] In 2006, about 1.9% of college student athletes in the United States used HMB as a dietary supplement and the use of HMB among these athletes appears to be increasing.^[12][27]

Side effects

The safety profile of HMB in adult humans has been well-established based upon evidence from clinical trials in humans and animal studies involving laboratory rats and certain livestock (i.e., pigs, broiler chickens, and turkeys).^{[9][12][16][23]} In humans, no adverse effects in young adults or older adults have been reported when HMB-Ca is taken in doses of 3 grams per day for up to a year.^[9][12][16] Studies on young adults taking 6 grams of HMB-Ca per day for up to two months have also reported no adverse effects.^[16] There is limited data on the safety of supplemental HMB in humans who are younger than 18 years old;^[2] however, studies with supplemental HMB on young, growing rats and livestock have reported no adverse effects based upon clinical chemistry or observable characteristics.^[2][23]

No clinical testing with supplemental HMB has been conducted on pregnant women;^[32] however, two animal studies have examined the effects of HMB supplementation in pregnant pigs on the offspring and reported no adverse effects on the fetus.^[23] As of 2016, Metabolic Technologies, Inc., the company that grants licenses to include HMB in dietary supplements, advises pregnant and lactating women not to take HMB due to a lack of safety studies conducted with this population.^[32]

Pharmacology

Diagram of the anabolic biomolecular signaling cascades that are involved in myofibrillar muscle protein synthesis and mitochondrial biogenesis in response to physical exercise and specific amino acids or their derivatives (primarily L-leucine and HMB).^[14]

Abbreviations and representations: 

 • PLD: phospholipase D
 • PA: phosphatidic acid
 • mTOR: mechanistic target of rapamycin
 • AMP: adenosine monophosphate
 • ATP: adenosine triphosphate
 • AMPK: AMP-activated protein kinase
 • PGC‐1α: peroxisome proliferator-activated receptor gamma coactivator-1α
 • S6K1: p70S6 kinase
 • 4EBP1: eukaryotic translation initiation factor 4E-binding protein 1
 • eIF4E: eukaryotic translation initiation factor 4E
 • RPS6: ribosomal protein S6
 • eEF2: eukaryotic elongation factor 2
 • RE: resistance exercise; EE: endurance exercise
 • Myo: myofibrillar; Mito: mitochondrial
 • AA: amino acids
 • HMB: β-hydroxy β-methylbutyric acid
 • ↑ represents activation
 • Τ represents inhibition

Resistance training stimulates muscle protein synthesis (MPS) for a period of up to 48 hours following exercise (shown by dotted line).^[33] Ingestion of a protein-rich meal at any point during this period will augment the exercise-induced increase in muscle protein synthesis (shown by solid lines).^[33]

Pharmacodynamics

As of May 2016, several components of the signaling cascade that mediate the HMB-induced increase in human skeletal muscle protein synthesis have been identified in vivo.^[10][15] Similar to L-leucine,^{[note 5]} 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 mTORC1, which leads to protein biosynthesis in the ribosome via phosphorylation of mTORC1's immediate targets (the p70S6 kinase and the translation repressor protein 4EBP1).^[14][15][35] Supplementation with HMB for one month in rats has also been shown to increase growth hormone and insulin-like growth factor 1 (IGF-1) signaling through their associated receptors in certain non-muscle tissues via an unknown mechanism, in turn promoting protein synthesis through increased mTOR phosphorylation.^[2][9][23] As of April 2016, it is not clear if long-term supplementation with HMB in humans produces a similar increase in growth hormone and IGF-1 signaling in skeletal muscle or any other tissues.^[2][9]

As of May 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 vivo.^[10][15] Unlike L-leucine,^{[note 6]} HMB attenuates muscle protein breakdown in an insulin-independent manner in humans.^[15] 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 skeletal muscle nuclei via unidentified mechanisms.^[9][15][35]

Based upon animal studies, HMB appears to be metabolized within skeletal muscle into cholesterol, which may then be incorporated into the muscle cell membrane, thereby enhancing membrane integrity and function.^{[13][18][23][28]} The effects of HMB on muscle protein metabolism may also facilitate the stabilization of muscle cell structure.^[23] One review suggested that the observed HMB-induced reduction in the plasma concentration of muscle damage 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.^{[note 4][23]}

HMB has been shown to stimulate the proliferation, differentiation, and 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 factors (e.g., MEF2).^[2][16][36] HMB-induced human myosatellite cell proliferation in vitro is mediated through the phosphorylation of the mitogen-activated protein kinases ERK1 and ERK2.^[16][23][36] HMB-induced human myosatellite differentiation and accelerated fusion of myosatellite cells into muscle tissue in vitro is mediated through the phosphorylation of Akt, a serine/threonine-specific protein kinase.^[16][23][36]

Pharmacokinetics

This graph shows the plasma concentration of HMB (in units of micromoles per liter of blood plasma) over time following ingestion of a 1 gram dose of the calcium or free acid form of HMB.^[2]

The free acid (HMB-FA) and monohydrated calcium salt (HMB-Ca) forms of HMB have different pharmacokinetics.^[2][19] HMB-FA is more readily absorbed into the bloodstream and has a longer elimination half-life (3 hours) relative to HMB-Ca (2.5 hours).^[2][19] Tissue uptake and utilization of HMB-FA is 25–40% higher than for HMB-Ca.^[2][19] The fraction of an ingested dose that is excreted in urine does not differ between the two forms.^[2]

After ingestion, HMB-Ca is converted to β-hydroxy β-methylbutyrate following dissociation of the calcium moiety in the gut.^[2] 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.^[2] Higher HMB-Ca doses increase the rate of absorption, resulting in a peak plasma HMB level (C_max) that is disproportionately greater than expected of a linear dose-response relationship and which occurs sooner relative to lower doses.^{[note 7][2]} Consumption of HMB-Ca with sugary substances slows the rate of HMB absorption, resulting in a lower peak plasma HMB level that occurs later.^{[note 7][2]}

HMB is eliminated via the kidneys, with roughly 10–40% of an ingested dose being excreted unchanged in urine.^[2][3] The remaining 60–90% of the dose is retained in tissues or excreted as HMB metabolites.^[2][3] The fraction of a given dose of HMB that is excreted unchanged in urine increases with the dose.^{[note 8][2]}

Biosynthesis

Human metabolic pathway for HMB and isovaleryl-CoA, relative to L-leucine.^[2][3][37] Of the two major pathways, L-leucine is mostly metabolized into isovaleryl-CoA, while only about 5% is metabolized into HMB.^[2][3][37]

HMB is synthesized in the human body through the metabolism of L-leucine, a branched-chain amino acid.^[37] In healthy individuals, approximately 60% of dietary L-leucine is metabolized after several hours, with roughly 5% (2–10% range) of dietary L-leucine being converted to HMB.^[3][9][37] Around 40% of dietary L-leucine is converted to acetyl-CoA, which is subsequently used in the synthesis of other compounds.^[37]

The vast majority of L-leucine metabolism is initially catalyzed by the branched-chain amino acid aminotransferase enzyme, producing α-ketoisocaproate (α-KIC).^[3][37] α-KIC is mostly metabolized by the mitochondrial enzyme branched-chain α-ketoacid dehydrogenase, which converts it to isovaleryl-CoA.^[3][37] Isovaleryl-CoA is subsequently metabolized by isovaleryl-CoA dehydrogenase and converted to β-methylcrotonyl-CoA (MC-CoA), which is used in the synthesis of acetyl-CoA and other compounds.^[37] During biotin deficiency, HMB can be synthesized from MC-CoA via enoyl-CoA hydratase and an unknown thioesterase enzyme,^[38][39][40] which convert MC-CoA into β-hydroxy β-methylbutyryl-CoA (HMB-CoA) and HMB-CoA into HMB respectively.^[40] A relatively small amount of α-KIC is metabolized in the liver by the cytosolic enzyme 4-hydroxyphenylpyruvate dioxygenase (KIC dioxygenase), which converts α-KIC to HMB.^[3][37][41] In healthy individuals, this minor pathway – which involves the conversion of L-leucine to α-KIC and then HMB – is the predominant route of HMB synthesis.^[3][37]

A small fraction of L-leucine metabolism – less than 5% in all tissues except the testes where it accounts for about 33% – is initially catalyzed by leucine aminomutase, producing β-leucine, which is subsequently metabolized into β-ketoisocaproate (β-KIC), β-ketoisocaproyl-CoA, and then acetyl-CoA by a series of uncharacterized enzymes.^[37][42] HMB could be produced via certain metabolites that are generated along this pathway, but as of 2015 the associated enzymes and reactions involved are not known.^[37]

Metabolism

The metabolism of HMB is initially catalyzed by an uncharacterized enzyme which converts it to HMB-CoA.^[37][39] HMB-CoA is metabolized by either enoyl-CoA hydratase or another uncharacterized enzyme, producing MC-CoA or hydroxymethylglutaryl-CoA (HMG-CoA) respectively.^[3][37] MC-CoA is then converted by the enzyme methylcrotonyl-CoA carboxylase to methylglutaconyl-CoA (MG-CoA), which is subsequently converted to HMG-CoA by methylglutaconyl-CoA hydratase.^[3][37][42] HMG-CoA is then cleaved into acetyl-CoA and acetoacetate by HMG-CoA lyase or used in the production of cholesterol via the mevalonate pathway.^[3][37]

Chemistry

Skeletal formula of butyric acid with the alpha, beta, and gamma carbons marked

Formula of β-hydroxy β-methylbutyric acid

HMB-FA is a monocarboxylic β-hydroxy acid and natural product with the chemical formula C₅H₁₀O₃.^[43][44] At room temperature, pure HMB-FA occurs as a transparent, colorless to light yellow liquid which is soluble in water.^[6][45][46] The pK_a of HMB-FA is 4.4,^[5] while the refractive index (${\displaystyle {\mathit {n}}_{\text{25°C}}^{\mathrm {\lambda =589nm} }}$) is 1.42.^[5]

Chemical structure

β-Hydroxy β-methylbutyric acid and β-hydroxy β-methylbutyrate are structural analogs of butyric acid and butyrate that have a hydroxy group and methyl group attached to the beta carbon of these compounds.^[43][44] By extension, β-hydroxybutyric acid and β-methylbutyric acid are also parent compounds of the free acid form of HMB.^[43][44] β-Hydroxy β-methylbutyric acid is the conjugate acid of β-hydroxy β-methylbutyrate, while β-hydroxy β-methylbutyrate is the conjugate base of β-hydroxy β-methylbutyric acid.^[44][47]

Synthesis

A variety of synthetic routes to β-hydroxy β-methylbutyric acid have been developed. The first reported chemical syntheses of β-hydroxy β-methylbutyric acid were from the oxidation of 2-methylpent-4-en-2-ol with chromic acid (CrO₄H₂) in 1877 by the Russian chemists Michael and Alexander Zaytsev,^[48] the oxidative cleavage of 4-methylpentane-1,2,4-triol with potassium permanganate (KMnO₄) in 1880 and 1889 by Alexius Schirokoff^[49] and Bergius Reformatsky^[50] respectively and by the oxidation with permanganate of 3-methylbutane-1,3-diol in 1892 by Kondakow.^[51]

A cycloaddition reaction between acetone and ketene depending on the conditions produce β-isovalerolactone^[52] or 4,4-dimethyloxetan-2-one.^[53] Hydrolysis of either of these lactones under basic conditions yields HMB. β-Hydroxy β-methylbutyric acid can also be prepared through the exhaustive halogenation of the methyl ketone of diacetone alcohol (the haloform reaction) with sodium hypobromite^[54] or sodium hypochlorite (NaOCl, more commonly known as bleach).^[5][55] Diacetone alcohol in turn may be prepared through the aldol condensation of acetone. The carboxylation of tert-butyl alcohol with carbon monoxide (CO) and Fenton's reagent (hydrogen peroxide and ferrous iron) has also been used to synthesize HMB.^[5][56] Alternatively HMB can be prepared through microbial oxidation of β-methylbutyric acid by the fungus Galactomyces reessii.^[57]

First synthetic routes to β-hydroxy β-methylbutyric acid

Synthetic routes to β-hydroxy β-methylbutyric acid

Detection in body fluids

HMB concentrations measured in healthy individuals

Biofluid	Age group	Concentration			Sources
		Mean	Range	Units
Blood	Adults (18+)	4.0	0–10.0	μM	[43]
CSF	Adults (18+)	4.0	2.0–6.0	μM	[43]
Breast milk	Adults (18+)	–	42–164	μg/L	[17]
Urine	Adults (18+)	–	3.2–25.0	μmol/mmol creatinine	[43]
Urine	Children (1–13)	–	0–64.4	μmol/mmol creatinine	[43]

Endogenously synthesized HMB has been detected and quantified in several human biofluids using nuclear magnetic resonance spectroscopy (NMR), liquid chromatography–mass spectrometry (LC–MS), and gas chromatography–mass spectrometry (GC–MS) methods.^[17][43] In the blood plasma and cerebrospinal fluid (CSF) of healthy adults, the average molar concentration of HMB has been quantified at 4.0 μM.^[43] In the urine of healthy individuals of any age, the excreted urinary concentration of HMB has been quantified in a range of 0–68 μmol/mmol creatinine.^[43] In the breast milk of healthy lactating women, HMB and L-leucine have been quantified in ranges of 42–164 μg/L and 2.1–88.5 mg/L.^[17] In comparison, HMB has been detected and quantified in the milk of healthy cows at a concentration of <20–29 μg/L.^[22] This concentration is far too low to be an adequate dietary source of HMB, but milk products could be fortified with HMB to confer benefits to skeletal muscle.^[22]

In a study where participants consumed 2.42 grams of pure HMB-FA while fasting, the average plasma HMB concentration increased from a basal level of 5.1 μM to 408 μM after 30 minutes.^[15] At 150 minutes post-ingestion, the average plasma HMB concentration among participants was quantified at 275 μM.^[15]

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 disorders.^[43] The following table lists some of these disorders along with the associated HMB concentrations detected in urine or blood plasma.^[43]

Abnormal HMB concentrations measured in disease states

Medical condition	Biofluid	Age group	Concentration			Sources
			Mean	Range	Units
Biotinidase deficiency^†	Blood	Adults (18+)	9.5	0–19.0	μM	[43]
Biotinidase deficiency^†	Blood	Children (1–13)	88.0	10.0–166.0	μM	[43]
Biotinidase deficiency^†	Urine	Children (1–13)	275.0	50.0–500.0	μmol/mmol creatinine	[43]
3-Methylglutaconic aciduria (Type I)^†	Urine	Children (1–13)	200.0	150.0–250.0	μmol/mmol creatinine	[43]
Eosinophilic esophagitis	Urine	Children (1–13)	247.4	0–699.4	μmol/mmol creatinine	[43]
Gastroesophageal reflux disease	Urine	Children (1–13)	119.8	5.5–234.0	μmol/mmol creatinine	[43]
HMG-CoA lyase deficiency^†	Urine	Children (1–13)	2030.0	60.0–4000.0	μmol/mmol creatinine	[43]
MC-CoA carboxylase deficiency^†	Urine	Children (1–13)	30350.0	1700.0–59000.0	μmol/mmol creatinine	[43]
A ^† indicates that the medical condition is a metabolic disorder.

History

The first reported chemical synthesis of β-hydroxy β-methylbutyric acid was published in 1877 by the Russian chemists Michael and Alexander Zaytsev.^[48] HMB was isolated from the bark of Erythrophleum couminga (a Madagascan tree) in 1941 by Leopold Ružička.^[58] The earliest reported isolation of β-hydroxy β-methylbutyric acid as a human metabolite was by Tanaka and coworkers in 1968 from a patient with isovaleric acidemia.^[59][60]

The effects of HMB on human skeletal muscle were first discovered by Steven L. Nissen at Iowa State University in the mid-1990s.^[7][24] Nissen founded a company called Metabolic Technologies, Inc. (MTI) around the time of his discovery, which subsequently acquired six HMB-related patents that the company has used to license the right to manufacture and incorporate HMB into dietary supplements.^[24][61] 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.^[61] MTI subsequently developed two HMB-containing products, Juven and Revigor, which Abbott Nutrition obtained the rights to market in 2003 and 2008 respectively.^[7][61] Since then, Abbott has marketed Juven as a medical food and the Revigor brand of HMB as an active ingredient in food products for athletes (e.g., certain formulations of Myoplex) and other medical foods (e.g., certain formulations of Ensure).^[7][20][61]

Notes

1. Synonyms and alternate spellings include: beta-hydroxy beta-methylbutyric acid, 3-hydroxyisovaleric acid, and beta-hydroxyisovaleric acid.
2. Since all T cells are CD3⁺, a measure of CD3⁺ cells is used as a general estimate of total T cells.^[29]
3. The estimated standard mean difference effect size for the increase in muscle mass in the HMB treatment groups relative to controls was 0.352 kilograms (0.78 lb) with a 95% confidence interval of 0.11–0.594 kilograms (0.24–1.31 lb).^[10] The seven randomized controlled trials that were included in the meta-analysis contained a total of 147 older adults in the HMB treatment groups and 140 older adults in the control groups.^[10] The studies had durations of 2–12 months and the majority lasted 2–3 months.^[10]
4. The effect of HMB on skeletal muscle damage has been assessed in studies on humans using four different biomarkers of muscle damage or protein breakdown: serum creatine kinase, serum lactate dehydrogenase, urinary urea nitrogen, and urinary 3-methylhistidine.^[2][12][13] 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%.^[2][12]
5. Approximately equal doses of pure HMB-FA (2.42 grams) and L-leucine (3.42 grams) do not produce statistically distinguishable anabolic effects, as measured by the fractional synthesis of myofibrillar proteins, in the skeletal muscle of living humans.^[15][34] At 150 minutes post-ingestion, these doses of HMB-FA and L-leucine increased muscle protein synthesis by ~70% and ~110% respectively in one study.^[15][34]
6. At 150 minutes post-ingestion, a 2.42 gram dose of pure HMB-FA decreased skeletal muscle protein breakdown in living humans by 57% in one study.^[15][34] The effect of L-leucine on muscle protein breakdown is entirely dependent upon insulin secretion and consequently was not measured in the same study.^[15] By comparison, the insulin-dependent reduction in muscle protein breakdown following an entire meal that contains L-leucine and carbohydrates is ~50% on average.^[15]
7. In one study, ingestion of a 1 gram dose of HMB-Ca by healthy volunteers produced a peak plasma HMB level of 120 μM at 2 hours following ingestion, while ingestion of a 3 gram dose of HMB-Ca produced a peak plasma HMB level of 487 μM at 1 hour following ingestion.^[2]
   Consumption of 3 grams of HMB-Ca with 75 grams of glucose resulted in a lower peak plasma HMB level of 352 μM which occurred later at 2 hours following ingestion.^[2]
8. In one study, ingestion of a 1 gram and 3 gram HMB dose resulted in the excretion of 14% and 28% of the dose as HMB in urine, respectively.^[2]

References

1. "Product Information: Ensure Enlive Advanced Therapeutic Nutrition Shake" (PDF). Abbott Nutrition. 9 August 2016. Retrieved 22 August 2016.
    • Use under medical supervision.
    • HMB + protein for muscle health.
   
   "Product Information: Juven" (PDF). Abbott Nutrition. 7 May 2016. Retrieved 22 August 2016.
    • Administer orally or as a modular via feeding tube ...
    • Use under medical supervision.
    • Nutravigor® (CaHMB, calcium β-hydroxy-β-methylbutyrate)
2. Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". Journal of the International Society of Sports Nutrition. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064. PMID 23374455. 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. ... 4. Thirty-eight mg·kg·BM-1 daily of HMB has been demonstrated to enhance skeletal muscle hypertrophy, strength, and power in untrained and trained populations when the appropriate exercise prescription is utilized. ... 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.
3. Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (April 2011). "HMB supplementation: clinical and athletic performance-related effects and mechanisms of action". Amino Acids. 40 (4): 1015–1025. doi:10.1007/s00726-010-0678-0. PMID 20607321. 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).
4. "Safety data sheet: 3-Hydroxy-3-methyl butyric acid". Alfa Aesar. 23 March 2005. Retrieved 9 November 2016.
5. Coffman DD, Cramer R, Mochel WE (June 1958). "Syntheses by Free-radical Reactions. V. A New Synthesis of Carboxylic Acids". Journal of the American Chemical Society. 80 (11): 2882–2887. doi:10.1021/ja01544a072.
6. "3-OH-isovaleric acid". ChemSpider. Royal Society of Chemistry. Retrieved 10 August 2016. Experimental Boiling Point: ... 128 °C / 7 mm ...
   Experimental solubility:
   Soluble in water
7. Linn J (13 May 2013). "Proteins in Human Health and Performance". Iowa State University. Retrieved 31 July 2016. 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.
8. Khamsi R (May 2013). "Rethinking the formula". Nature Medicine. 19 (5): 525–529. doi:10.1038/nm0513-525. PMID 23652097. 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. ... Abbott Nutrition's Juven provides nutrients to people with HIV or AIDS experiencing excessive weight loss due to disease
9. Brioche T, Pagano AF, Py G, Chopard A (August 2016). "Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention". Molecular Aspects of Medicine. 50: 56–87. doi:10.1016/j.mam.2016.04.006. PMID 27106402. In conclusion, HMB treatment clearly appears to be a safe potent strategy against sarcopenia, and more generally against muscle wasting, because HMB improves muscle mass, muscle strength, and physical performance. It seems that HMB is able to act on three of the four major mechanisms involved in muscle deconditioning (protein turnover, apoptosis, and the regenerative process), whereas it is hypothesized to strongly affect the fourth (mitochondrial dynamics and functions). Moreover, HMB is cheap (~30– 50 US dollars per month at 3 g per day) and may prevent osteopenia (Bruckbauer and Zemel, 2013; Tatara, 2009; Tatara et al., 2007, 2008, 2012) and decrease cardiovascular risks (Nissen et al., 2000). For all these reasons, HMB should be routinely used in muscle-wasting conditions especially in aged people. ... 3 g of CaHMB taken three times a day (1 g each time) is the optimal posology, which allows for continual bioavailability of HMB in the body (Wilson et al., 2013)
10. Wu H, Xia Y, Jiang J, Du H, Guo X, Liu X, Li C, Huang G, Niu K (September 2015). "Effect of beta-hydroxy-beta-methylbutyrate supplementation on muscle loss in older adults: a systematic review and meta-analysis". Archives of Gerontology and Geriatrics. 61 (2): 168–175. doi:10.1016/j.archger.2015.06.020. PMID 26169182. CONCLUSION: Beta-hydroxy-beta-methylbutyrate supplementation contributed to preservation of muscle mass in older adults. HMB supplementation may be useful in the prevention of muscle atrophy induced by bed rest or other factors. Further studies are needed to determine the precise effects of HMB on muscle strength and physical function in older adults. ... 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).
11. Argilés JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Mañas L (September 2016). "Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease". Journal of the American Medical Directors Association. 17 (9): 789–796. doi:10.1016/j.jamda.2016.04.019. PMID 27324808. Studies suggest dietary protein and leucine or its metabolite β-hydroxy β-methylbutyrate (HMB) can improve muscle function, in turn improving functional performance. ... These have identified the leucine metabolite β-hydroxy β-methylbutyrate (HMB) as a potent stimulator of protein synthesis as well as an inhibitor of protein breakdown in the extreme case of cachexia. ... 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. ... 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. ... 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. ... 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. ... The overall treatment of muscle atrophy should include dietary supplementation with HMB, although the optimal dosage for each condition is still under investigation. ...
    Figure 4: Treatments for sarcopenia. It is currently recommended that patients at risk of or suffering from sarcopenia consume a diet high in protein, engage in resistance exercise, and take supplements of the leucine metabolite HMB.
12. Momaya A, Fawal M, Estes R (April 2015). "Performance-enhancing substances in sports: a review of the literature". Sports Medicine. 45 (4): 517–531. doi:10.1007/s40279-015-0308-9. PMID 25663250. Currently, HMB is available as an over-the-counter supplement. The drug is not tested for nor banned by any sporting organization. ... 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. ... 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]. ... No serious adverse effects from HMB consumption have been reported.
13. Luckose F, Pandey MC, Radhakrishna K (2015). "Effects of amino acid derivatives on physical, mental, and physiological activities". Critical Reviews in Food Science and Nutrition. 55 (13): 1793–1807. doi:10.1080/10408398.2012.708368. PMID 24279396. 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. ... 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). ... 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.
14. Brook MS, Wilkinson DJ, Phillips BE, Perez-Schindler J, Philp A, Smith K, Atherton PJ (January 2016). "Skeletal muscle homeostasis and plasticity in youth and ageing: impact of nutrition and exercise". Acta Physiologica. 216 (1): 15–41. doi:10.1111/apha.12532. PMC 4843955. PMID 26010896. 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.
15. Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ, Atherton PJ (June 2013). "Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism" (PDF). The Journal of Physiology. 591 (11): 2911–2923. doi:10.1113/jphysiol.2013.253203. PMC 3690694. PMID 23551944. The stimulation of MPS through mTORc1-signalling following HMB exposure is in agreement with pre-clinical studies (Eley et al. 2008). ... Furthermore, there was clear divergence in the amplitude of phosphorylation for 4EBP1 (at Thr37/46 and Ser65/Thr70) and p70S6K (Thr389) in response to both Leu and HMB, with the latter showing more pronounced and sustained phosphorylation. ... Nonetheless, as the overall MPS response was similar, this cellular signalling distinction did not translate into statistically distinguishable anabolic effects in our primary outcome measure of MPS. ... Interestingly, although orally supplied HMB produced no increase in plasma insulin, it caused a depression in MPB (−57%). Normally, postprandial decreases in MPB (of ~50%) are attributed to the nitrogen-sparing effects of insulin since clamping insulin at post-absorptive concentrations (5 μU ml⁻¹) while continuously infusing AAs (18 g h⁻¹) did not suppress MPB (Greenhaff et al. 2008), which is why we chose not to measure MPB in the Leu group, due to an anticipated hyperinsulinaemia (Fig. 3C). Thus, HMB reduces MPB in a fashion similar to, but independent of, insulin. These findings are in-line with reports of the anti-catabolic effects of HMB suppressing MPB in pre-clinical models, via attenuating proteasomal-mediated proteolysis in response to LPS (Eley et al. 2008).
16. Molfino A, Gioia G, Rossi Fanelli F, Muscaritoli M (December 2013). "Beta-hydroxy-beta-methylbutyrate supplementation in health and disease: a systematic review of randomized trials". Amino Acids. 45 (6): 1273–1292. doi:10.1007/s00726-013-1592-z. PMID 24057808. Normally, an individual metabolizes 60 g of L-LEU to obtain 3 g of HMB but a 70 kg person produces 0.2–0.4 g of HMB per day, depending on the dose of LEU in the diet (Van Koevering and Nissen 1992). ... The usual dose of 3 g/day may be routinely recommended to maintain or improve muscle mass and function in health and disease. The safety profile of HMB is unequivocal. ... These results show that HMB/ARG/GLN can be safely used to treat AIDS- and cancer-related muscle wasting (Rathmacher et al. 2004). Berk et al. (2008) showed a strong trend towards higher FFM and BM in HMB/ARG/GLN-supplemented patients but they did not adequately test the ability of HMB/ARG/GLN to reverse or prevent cancer cachexia because most of patients did not complete the study.
17. Ehling S, Reddy TM (September 2015). "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 of Agricultural and Food Chemistry. 63 (34): 7567–7573. doi:10.1021/acs.jafc.5b02563. PMID 26271627.
18. Landi F, Calvani R, Tosato M, Martone AM, Ortolani E, Savera G, D'Angelo E, Sisto A, Marzetti E (May 2016). "Protein Intake and Muscle Health in Old Age: From Biological Plausibility to Clinical Evidence". Nutrients. 8 (5): 295. doi:10.3390/nu8050295. PMC 4882708. PMID 27187465. HMB 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. ... 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].
19. Fuller JC, Sharp RL, Angus HF, Khoo PY, Rathmacher JA (November 2015). "Comparison of availability and plasma clearance rates of β-hydroxy-β-methylbutyrate delivery in the free acid and calcium salt forms". The British Journal of Nutrition. 114 (9): 1403–1409. doi:10.1017/S0007114515003050. PMID 26373270. 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. ... In conclusion, HMB-FA in capsule form improves clearance rate and availability of HMB compared with Ca-HMB in capsule form.
20. "Abbott Nutrition Overview" (PDF). Abbott. Abbott Laboratories. Retrieved 3 September 2016.
21. Wilson GJ, Wilson JM, Manninen AH (January 2008). "Effects of beta-hydroxy-beta-methylbutyrate (HMB) on exercise performance and body composition across varying levels of age, sex, and training experience: A review". Nutrition & Metabolism. 5: 1. doi:10.1186/1743-7075-5-1. PMC 2245953. PMID 18173841.
22. Ehling S, Reddy TM (February 2014). "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 of Agricultural and Food Chemistry. 62 (7): 1506–1511. doi:10.1021/jf500026s. PMID 24495238.
23. Szcześniak KA, Ostaszewski P, Fuller JC, Ciecierska A, Sadkowski T (June 2015). "Dietary supplementation of β-hydroxy-β-methylbutyrate in animals - a review". Journal of Animal Physiology and Animal Nutrition. 99 (3): 405–417. doi:10.1111/jpn.12234. PMID 25099672. 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. ... 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) ... 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.
24. Fitzgerald M (May 2014). Diet Cults: The Surprising Fallacy at the Core of Nutrition Fads and a Guide to Healthy Eating for the Rest of Us. Pegasus Books. p. 148. ISBN 978-1-60598-595-4. Retrieved 31 July 2016. HMB was discovered in the mid-1990s by Steve Nissen, a researcher at Iowa State University
25. Rippe JM (March 2013). "Beta-Hydroxy beta-methylbutyrate". Lifestyle Medicine (2nd ed.). CRC Press. p. 724. ISBN 978-1-4398-4544-8. Retrieved 15 August 2016.
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28. Rahman A, Wilund K, Fitschen PJ, Jeejeebhoy K, Agarwala R, Drover JW, Mourtzakis M (July 2014). "Elderly persons with ICU-acquired weakness: the potential role for β-hydroxy-β-methylbutyrate (HMB) supplementation?". JPEN. Journal of Parenteral and Enteral Nutrition. 38 (5): 567–575. doi:10.1177/0148607113502545. PMID 24072740. More than 20 publications in humans have demonstrated benefit with HMB supplementation associated with increased lean body mass without fat gain, improved markers of muscle strength, and decreased onset of muscle soreness with training and reduced markers of muscle damage. ... 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. ... 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.
29. Barth SD, Kaaks R, Johnson T, Katzke V, Gellhaus K, Schulze JJ, Olek S, Kühn T (September 2016). "The Ratio of Regulatory (FOXP3+) to Total (CD3+) T Cells Determined by Epigenetic Cell Counting and Cardiovascular Disease Risk: A Prospective Case-cohort Study in Non-diabetics". EBioMedicine. 11: 151–156. doi:10.1016/j.ebiom.2016.07.035. PMID 27499494.
30. Berk L, James J, Schwartz A, Hug E, Mahadevan A, Samuels M, Kachnic L (October 2008). "A randomized, double-blind, placebo-controlled trial of a beta-hydroxyl beta-methyl butyrate, glutamine, and arginine mixture for the treatment of cancer cachexia (RTOG 0122)". Supportive Care in Cancer. 16 (10): 1179–1188. doi:10.1007/s00520-008-0403-7. PMID 18293016. RESULTS: Only 37% of the patients completed protocol treatment. ... CONCLUSION: This trial was unable to adequately test the ability of beta-hydroxy beta-methylbutyrate, glutamine, and arginine to reverse or prevent lean body mass wasting among cancer patients. ... However, there was a strong trend towards an increased body mass among patients taking the Juven compound
31. Mullin GE (February 2014). "Nutrition supplements for athletes: potential application to malnutrition". Nutrition in Clinical Practice. 29 (1): 146–147. doi:10.1177/0884533613516130. PMID 24336486. 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.
32. "Who should not take HMB?". Metabolic Technologies, Inc. Retrieved 23 August 2016. Pregnant or lactating women are advised against taking HMB because safety studies have not yet been conducted for these populations.
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35. Dutt V, Gupta S, Dabur R, Injeti E, Mittal A (September 2015). "Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action". Pharmacological Research. 99: 86–100. doi:10.1016/j.phrs.2015.05.010. PMID 26048279. 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]. ... 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).
36. Kornasio R, Riederer I, Butler-Browne G, Mouly V, Uni Z, Halevy O (May 2009). "Beta-hydroxy-beta-methylbutyrate (HMB) stimulates myogenic cell proliferation, differentiation and survival via the MAPK/ERK and PI3K/Akt pathways". Biochimica et Biophysica Acta. 1793 (5): 755–763. doi:10.1016/j.bbamcr.2008.12.017. PMID 19211028.
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    Figure 8.57: Metabolism of L-LEUCINE
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External links

• Beta-Hydroxyisovaleric acid at the US National Library of Medicine Medical Subject Headings (MeSH)