?-Hydroxy ?-methylbutyric acid (HMB), also known as ?-hydroxy ?-methylbutyrate, is a naturally produced substance in humans that is used as dietary supplement and as an ingredient in some medical food products. HMB can reduce the loss of lean body mass in individuals experiencing age-related muscle loss, but more research is needed to determine how it affects muscle strength and function in older adults. In healthy adults, supplementation with HMB has been shown to increase gains in muscle size, muscle strength, lean body mass, reduce skeletal muscle damage, and speed recovery from exercise. HMB produces these effects in part by stimulating the production of proteins and inhibiting the breakdown of proteins in muscle tissue. Medical reviews have found no issues with safety from long-term use as a dietary supplement in adults.
HMB is a metabolite of L-leucine that is produced in the body through oxidation of the ketoacid of L-leucine (?-ketoisocaproic acid). 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. A healthy adult produces approximately 0.3 grams per day, while supplemental HMB is usually taken in doses of 3-6 grams per day. HMB is sold worldwide as a dietary supplement at a cost of about US$30-50 per month when taking 3 grams per day. HMB is also contained in several nutritional products, including certain formulations of Ensure, Juven, and Myoplex. Small amounts of HMB are present in certain foods, such as alfalfa, asparagus, avocados, cauliflower, grapefruit, catfish, and milk.
The effects of HMB on human skeletal muscle were first discovered by Steven L. Nissen at Iowa State University in the mid-1990s. It is added to certain medical foods that are intended to provide nutritional support for people with muscle wasting due to cancer or HIV/AIDS and to promote wound healing. 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. 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.
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Uses
Available forms
HMB is sold worldwide as an over-the-counter dietary supplement in the free acid form, ?-hydroxy ?-methylbutyric acid (HMB-FA), and as a monohydrated calcium salt of the conjugate base, calcium ?-hydroxy ?-methylbutyrate monohydrate (HMB-Ca, CaHMB). It is sold at a cost of about US$30-50 per month when taken in doses of 3 grams per day. HMB is also contained in several nutritional products and medical foods marketed by Abbott Laboratories (e.g., certain formulations of Ensure, Juven, and Myoplex), and is present in insignificant quantities in certain foods, such as alfalfa, asparagus, avocados, cauliflower, grapefruit, catfish, and milk.
Medical
Some branded products that contain HMB (i.e., certain formulations of Ensure and Juven) are medical foods 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. 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, has been shown to improve lean body mass during clinical trials in individuals with AIDS and cancer, but not rheumatoid cachexia. 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. 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; 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. Further research involving the treatment of cancer cachexia with Juven over a period of several months is required to adequately determine treatment efficacy.
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 has been studied in clinical trials as an adjunct therapy in conjunction with resistance exercise. HMB supplementation may also prevent muscle atrophy during bed rest, but more research is needed to determine its efficacy for this purpose. 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; 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. 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. HMB does not appear to significantly affect fat mass in older adults. More research is needed to determine the precise effects on muscle strength and function in this age group.
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. 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; however, as of June 2016 the best dosing regimen for muscle wasting conditions is still being investigated.
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), muscle strength, and lean body mass, reduces exercise-induced skeletal muscle damage, and may expedite recovery from high-intensity exercise. 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.
The inhibition of exercise-induced skeletal muscle damage by HMB is affected by the time that it is used relative to exercise. 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.
As of 2015, HMB has not been banned by the NCAA, WADA, or any other prominent national or international athletic organization. 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.
Side effects
The safety profile of HMB in adult humans is based upon evidence from clinical trials in humans and animal studies. 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. Studies on young adults taking 6 grams of HMB-Ca per day for up to two months have also reported no adverse effects. There is limited data on the safety of supplemental HMB in humans who are younger than 18 years old; however, studies with supplemental HMB on young, growing rats and livestock have reported no adverse effects based upon clinical chemistry or observable characteristics.
No clinical testing with supplemental HMB has been conducted on pregnant women; 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. 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.
Pharmacology
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. Similar to 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 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). 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. 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.
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. Unlike L-leucine, HMB attenuates muscle protein breakdown in an insulin-independent manner in humans. 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.
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. The effects of HMB on muscle protein metabolism may also facilitate the stabilization of muscle cell structure. 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.
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). HMB-induced human myosatellite cell proliferation in vitro is mediated through the phosphorylation of the mitogen-activated protein kinases ERK1 and ERK2. 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.
Pharmacokinetics
The free acid (HMB-FA) and monohydrated calcium salt (HMB-Ca) forms of HMB have different pharmacokinetics. 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). Tissue uptake and utilization of HMB-FA is 25-40% higher than for HMB-Ca. The fraction of an ingested dose that is excreted in urine does not differ between the two forms.
After ingestion, HMB-Ca is converted to ?-hydroxy ?-methylbutyrate following dissociation of the calcium moiety in the gut. 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. Higher HMB-Ca doses increase the rate of absorption, resulting in a peak plasma HMB level (Cmax) that is disproportionately greater than expected of a linear dose-response relationship and which occurs sooner relative to lower doses. Consumption of HMB-Ca with sugary substances slows the rate of HMB absorption, resulting in a lower peak plasma HMB level that occurs later.
HMB is eliminated via the kidneys, with roughly 10-40% of an ingested dose being excreted unchanged in urine. The remaining 60-90% of the dose is retained in tissues or excreted as HMB metabolites. The fraction of a given dose of HMB that is excreted unchanged in urine increases with the dose.
Biosynthesis
HMB is synthesized in the human body through the metabolism of L-leucine, a branched-chain amino acid. 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. Around 40% of dietary L-leucine is converted to acetyl-CoA, which is subsequently used in the synthesis of other compounds.
The vast majority of L-leucine metabolism is initially catalyzed by the branched-chain amino acid aminotransferase enzyme, producing ?-ketoisocaproate (?-KIC). ?-KIC is mostly metabolized by the mitochondrial enzyme branched-chain ?-ketoacid dehydrogenase, which converts it to isovaleryl-CoA. Isovaleryl-CoA is subsequently metabolized by isovaleryl-CoA dehydrogenase and converted to ?-methylcrotonyl-CoA (MC-CoA), which is used in the synthesis of acetyl-CoA and other compounds. During biotin deficiency, HMB can be synthesized from MC-CoA via enoyl-CoA hydratase and an unknown thioesterase enzyme, which convert MC-CoA into ?-hydroxy ?-methylbutyryl-CoA (HMB-CoA) and HMB-CoA into HMB respectively. A relatively small amount of ?-KIC is metabolized in the liver by the cytosolic enzyme 4-hydroxyphenylpyruvate dioxygenase (KIC dioxygenase), which converts ?-KIC to HMB. In healthy individuals, this minor pathway - which involves the conversion of L-leucine to ?-KIC and then HMB - is the predominant route of HMB synthesis.
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 ?-leucine, which is subsequently metabolized into ?-ketoisocaproate (?-KIC), ?-ketoisocaproyl-CoA, and then acetyl-CoA by a series of uncharacterized enzymes. 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.
Metabolism
The metabolism of HMB is initially catalyzed by an uncharacterized enzyme which converts it to HMB-CoA. HMB-CoA is metabolized by either enoyl-CoA hydratase or another uncharacterized enzyme, producing MC-CoA or hydroxymethylglutaryl-CoA (HMG-CoA) respectively. 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. 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.
Chemistry
HMB-FA is a monocarboxylic ?-hydroxy acid and natural product with the chemical formula C5H10O3. At room temperature, pure HMB-FA occurs as a transparent, colorless to light yellow liquid which is soluble in water. The pKa of HMB-FA is 4.4, while the refractive index () is 1.42.
Chemical structure
?-Hydroxy ?-methylbutyric acid and ?-hydroxy ?-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. By extension, ?-hydroxybutyric acid and ?-methylbutyric acid are also parent compounds of the free acid form of HMB. ?-Hydroxy ?-methylbutyric acid is the conjugate acid of ?-hydroxy ?-methylbutyrate, while ?-hydroxy ?-methylbutyrate is the conjugate base of ?-hydroxy ?-methylbutyric acid.
Synthesis
A variety of synthetic routes to ?-hydroxy ?-methylbutyric acid have been developed. The first reported chemical syntheses of ?-hydroxy ?-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, the oxidative cleavage of 4-methylpentane-1,2,4-triol with potassium permanganate (KMnO4) in 1880 and 1889 by Alexius Schirokoff and Bergius Reformatsky respectively and by the oxidation with permanganate of 3-methylbutane-1,3-diol in 1892 by Kondakow.
A cycloaddition reaction between acetone and ketene depending on the conditions produce ?-isovalerolactone or 4,4-dimethyloxetan-2-one. Hydrolysis of either of these lactones under basic conditions yields HMB. ?-Hydroxy ?-methylbutyric acid can also be prepared through the exhaustive halogenation of the methyl ketone of diacetone alcohol (the haloform reaction) with sodium hypobromite or sodium hypochlorite (NaOCl, more commonly known as bleach). 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. Alternatively HMB can be prepared through microbial oxidation of ?-methylbutyric acid by the fungus Galactomyces reessii.
Detection in body fluids
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. In the blood plasma and cerebrospinal fluid (CSF) of healthy adults, the average molar concentration of HMB has been quantified at 4.0 ?M. In the urine of healthy individuals of any age, the excreted urinary concentration of HMB has been quantified in a range of 0-68 ?mol/mmol creatinine. In the breast milk of healthy lactating women, HMB and L-leucine have been quantified in ranges of 42-164 ?g/L and 2.1-88.5 mg/L. In comparison, HMB has been detected and quantified in the milk of healthy cows at a concentration of <20-29 ?g/L. 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.
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 ?M to 408 ?M after 30 minutes. At 150 minutes post-ingestion, the average plasma HMB concentration among participants was quantified at 275 ?M.
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. The following table lists some of these disorders along with the associated HMB concentrations detected in urine or blood plasma.
History
The first reported chemical synthesis of ?-hydroxy ?-methylbutyric acid was published in 1877 by the Russian chemists Michael and Alexander Zaytsev. HMB was isolated from the bark of Erythrophleum couminga (a Madagascan tree) in 1941 by Leopold Ru?i?ka. The earliest reported isolation of ?-hydroxy ?-methylbutyric acid as a human metabolite was by Tanaka and coworkers in 1968 from a patient with isovaleric acidemia.
The effects of HMB on human skeletal muscle were first discovered by Steven L. Nissen at Iowa State University in the mid-1990s. 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. 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. MTI subsequently developed two HMB-containing products, Juven and Revigor, which Abbott Nutrition obtained the rights to market in 2003 and 2008 respectively. 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).
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