An overview on leucine metabolites alpha-ketoisocaproate (KIC) and beta-hydroxi-beta-methyl butyrate (HMB) in skeletal muscle function and sports performance

Alpha-ketoisocaproate (KIC) and Beta hydroxy-beta methylbutyrate (HMB) are metabolites of the amino acid leucine. The first step in HMB metabolism is the reversible transamination of leucine to KIC, which occurs mainly extrahepatically. Following this enzymatic reaction, KIC is converted to HMB by two routes. through the cytosolic enzyme KIC dioxygenase. or through formation of isovaleryl-CoA by branched-chain ketoacid dehydrogenase (BCKD) in liver, which after some steps results in HMB formation. Under normal conditions the majority of KIC is converted into isovaleryl-CoA, with approximately 5% of leucine consumed metabolized into HMB. HMB and KIC have been proposed to enhance physical performance and muscle hypertrophy via their effects on muscle proteolysis and protein synthesis. Studies investigating the mechanisms by which HMB promotes increases in strength and muscle hypertrophy are still in preliminary stages. Based on the results of these studies, it is postulated that enhancements from leucine metabolite supplementation involve the following mechanisms. improvements in sarcolemal integrity. upregulation of IGF-1 gene expression in skeletal muscle and IGF-1 production by liver. stimulation of protein synthesis by activating the mTOR signaling pathway. suppression of skeletal muscle proteolysis by the inhibition of the ubiquitin-proteasome system. and modulation of lipopolysaccharides, tumor necrosis factor alpha (TNF-alpha) and angiotensin 2, attenuating protein synthesis depression in catabolic conditions. In turn, KIC has been used in conjunction with glycine and arginine (marketed as GAKIC). Acute GAKIC ingestion has been demonstrated to significantly enhance human performance during intense muscle contractions and repeated cycling sprints. The proposed mechanism of action of GAKIC includes. removal of deaminated nitrogen waste produced during exercise. regeneration of L-leucine via leucine dehydrogenase enzyme. promoting HMB synthesis via KIC dioxygenase enzyme. reducing ammonia levels during intense exercise. and increasing ATP levels through Isovaleryl-CoA and Acetyl-CoA formation. Interestingly, KIC ingestion does not result in the same effects of GAKIC, suggesting that glycine and arginine are both necessary for the enhanced performance. In this chapter the effects of HMB and KIC on muscle function and sports performance will be discussed, based on recent research findings.