Branched-chain Amino Acids: Catabolism in Skeletal Muscle and Implications for Muscle and Whole-body Metabolism

Abstract

Branched-chain amino acids (BCAAs) are critical for skeletal muscle and whole-body anabolism and energy homeostasis. They also serve as signaling molecules, for example, being able to activate mammalian/mechanistic target of rapamycin complex 1 (mTORC1). This has implication for macronutrient metabolism. However, elevated circulating levels of BCAAs and of their ketoacids as well as impaired catabolism of these amino acids (AAs) are implicated in the development of insulin resistance and its sequelae, including type 2 diabetes, cardiovascular disease, and of some cancers, although other studies indicate supplements of these AAs may help in the management of some chronic diseases. Here, we first reviewed the catabolism of these AAs especially in skeletal muscle as this tissue contributes the most to whole body disposal of the BCAA. We then reviewed emerging mechanisms of control of enzymes involved in regulating BCAA catabolism. Such mechanisms include regulation of their abundance by microRNA and by post translational modifications such as phosphorylation, acetylation, and ubiquitination. We also reviewed implications of impaired metabolism of BCAA for muscle and whole-body metabolism. We comment on outstanding questions in the regulation of catabolism of these AAs, including regulation of the abundance and post-transcriptional/post-translational modification of enzymes that regulate BCAA catabolism, as well the impact of circadian rhythm, age and mTORC1 on these enzymes. Answers to such questions may facilitate emergence of treatment/management options that can help patients suffering from chronic diseases linked to impaired metabolism of the BCAAs.

Altered Serum Acylcarnitines Profile after a Prolonged Stay in Intensive Care

“…Short-chain AC can be derivates from alternative energy sources, such as BCAA [ 3 , 18 ]. Systemic inflammation, as observed in sepsis and trauma, induces catabolism, and also a leucine release from visceral tissues, leading to an increase in BCAA, prompting the utilization of carnitine and the production of C3, C4 and C5 derivates [ 18 , 19 ]. In the present study, we found a weak correlation between short-chain AC concentration and BCAA concentration, reinforcing this hypothesis.…”

Central and Peripheral Fatigue in Physical Exercise Explained: A Narrative Review

“… Once glycogen is depleted, brain chain amino acids (BCAA) are oxidized to be used in ATP resynthesis; BCAAs follow the same mechanism as free fatty acids to overcome the brain barrier, where they compete with free tryptophan in the bloodstream. When the BCAA/free tryptophan ratio decreases, serotonin may be accumulated in the brain [ 97 , 98 ], producing a feeling of lethargy and a loss of the neural drive [ 2 ]; thus, CNS fatigue. …”

Metabolomic Profiling of Angiotensin-II-Induced Abdominal Aortic Aneurysm in Ldlr−/− Mice Points to Alteration of Nitric Oxide, Lipid, and Energy Metabolisms

“…Mechanistically, the increase in BCAA/Gln can be explained by an inhibition of muscular mitochondrial branched-chain aminotransferase (BCAT2) resulting in decreased BCAA catabolism and glutamine production. BCAT2 catalyzes deamination of three BCAA whilst transferring the amino group to α-ketoglutarate (α-KG), leading to the formation of branched-chain α-ketoacid and glutamate [ 26 ]. Glutamate can be eventually aminated to glutamine by glutamine synthetase.…”