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 () and monohydrated calcium salt () 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 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, is converted to 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 of an ingested dose being excreted unchanged in urine. The remaining 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. Metabolism The metabolism of HMB is catalyzed by an uncharacterized enzyme which converts it to (). HMB-CoA is metabolized by either enoyl-CoA hydratase or another uncharacterized enzyme, producing β-methylcrotonyl-CoA () or hydroxymethylglutaryl-CoA () respectively. is then converted by the enzyme methylcrotonyl-CoA carboxylase to methylglutaconyl-CoA (), which is subsequently converted to by methylglutaconyl-CoA hydratase. is then cleaved into and acetoacetate by lyase or used in the production of cholesterol via the mevalonate pathway. Biosynthesis HMB is synthesized in the human body through the metabolism of , a branched-chain amino acid. In healthy individuals, approximately 60% of dietary is metabolized after several hours, with roughly 5% ( range) of dietary being converted to .