β-Hydroxy β-methylbutyric acid[note 1] (HMB), otherwise known as its conjugate base, β-hydroxy β-methylbutyrate, is a naturally produced substance in humans that is used as a dietary supplement and as an ingredient in certain medical foods that are intended to promote wound healing and provide nutritional support for people with muscle wasting due to cancer or HIV/AIDS.

The effects of HMB on human skeletal muscle were first discovered by Steven L. Nissen at Iowa State University in the mid-1990s.

[11][12] Preliminary clinical evidence suggests that HMB supplementation may also prevent muscle atrophy during bed rest.

[27] 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.

[12][14] These effects of HMB are more pronounced in untrained individuals and athletes who perform high intensity resistance or aerobic exercise.

[1] 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 g/kg of body weight per day.

[38] Several components of the signaling cascade that mediates the HMB-induced increase in human skeletal muscle protein synthesis have been identified in vivo.

[1][16][31] 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.

[note 3][31] 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).

[1][17][42] HMB-induced human myosatellite cell proliferation in vitro is mediated through the phosphorylation of the mitogen-activated protein kinases ERK1 and ERK2.

[17][31][42] The free acid (HMB-FA) and monohydrated calcium salt (HMB-Ca) forms of HMB have different pharmacokinetics.

[1] 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.

[43][46] HMB-CoA is metabolized by either enoyl-CoA hydratase or another uncharacterized enzyme, producing β-methylcrotonyl-CoA (MC-CoA) or hydroxymethylglutaryl-CoA (HMG-CoA) respectively.

The vast majority of L-leucine metabolism is initially catalyzed by the branched-chain amino acid aminotransferase enzyme, producing α-ketoisocaproate (α-KIC).

[50][51] At room temperature, pure β-hydroxy β-methylbutyric acid occurs as a transparent, colorless to light yellow liquid which is soluble in water.

[50] It is a structural analog of butyric acid with a hydroxyl functional group and a methyl substituent located on its beta carbon.

[61] An organometallic approach to HMB involves the carboxylation of tert-butyl alcohol with carbon monoxide and Fenton's reagent (hydrogen peroxide and ferrous iron).

[65][50] In the blood plasma and cerebrospinal fluid (CSF) of healthy adults, the average molar concentration of HMB has been measured at 4.0 micromolar (μM).

[15] In the urine of healthy individuals of any age, the excreted urinary concentration of HMB has been measured in a range of 0–68 micromoles per millimole (μmol/mmol) of creatinine.

[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.

[67] The earliest reported isolation of HMB as a human metabolite was by Tanaka and coworkers in 1968 from a patient with isovaleric acidemia.

[19][70][71] 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.

[70] MTI subsequently developed two HMB-containing products, Juven and Revigor, to which Abbott Nutrition obtained the market rights in 2003 and 2008 respectively.