Branched‐Chain Amino Acids and Mitochondrial Biogenesis: An Overview and Mechanistic Summary

Abstract

Branched‐chain amino acids (BCAA) are essential in the diet and promote several vital cell responses which may have benefits for health and athletic performance, as well as disease prevention. While BCAA are well‐known for their ability to stimulate muscle protein synthesis, their effects on cell energetics are also becoming well‐documented, but these receive less attention. In this review, much of the current evidence demonstrating BCAA ability (as individual amino acids or as part of dietary mixtures) to alter regulators of cellular energetics with an emphasis on mitochondrial biogenesis and related signaling is highlighted. Several studies have shown, both in vitro and in vivo, that BCAA (either individual or as a mixture) may promote signaling associated with increased mitochondrial biogenesis including the upregulation of master regulator of mitochondrial biogenesis peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α), as well as numerous downstream targets and related function. However, sparse data in humans and the difficulty of controlling variables associated with feeding studies leave the physiological relevance of these findings unclear. Future well‐controlled diet studies will be needed to assess if BCAA consumption is associated with increased mitochondrial biogenesis and improved metabolic outcomes in healthy and/or diseased human populations.

Branched‐Chain Amino Acid Accumulation Fuels the Senescence‐Associated Secretory Phenotype

“…[97] The underlying mechanisms for these modulations are evidently associated with the mTORC1 and Sirtuin 1 pathways and the regulation of TCA cycle enzyme activities. [97] Furthermore, BCAA restriction has shown promise in improving insulin resistance and reducing body fat by modulating the energy-regulating hormone fibroblast growth factor 21 (FGF21) to enhance metabolic health. [98] BCAAs are often studied collectively due to their shared structural and metabolic features.…”

“…[ 97 ] BCAAs, along with related metabolites, have been shown to modulate mitochondrial biogenesis and functions. [ 97 ] The underlying mechanisms for these modulations are evidently associated with the mTORC1 and Sirtuin 1 pathways and the regulation of TCA cycle enzyme activities. [ 97 ] Furthermore, BCAA restriction has shown promise in improving insulin resistance and reducing body fat by modulating the energy‐regulating hormone fibroblast growth factor 21 (FGF21) to enhance metabolic health.…”

Mitochondrial involvement in sarcopenia

“…In healthy skeletal muscle, leucine acutely increases protein synthesis in the postprandial state through mTOR activation by various signals, including acetyl CoA, leucyl‐tRNA and sestrin 154 . Perhaps to meet energy demand from this anabolic stimulation, 155 it is suggested by rodent pre‐clinical studies that leucine also triggers an adaptive catabolic response that involves AMPK and that increases skeletal muscle mitochondrial biogenesis, mtDNA content, fatty acid oxidation and glucose uptake 156 . The apparently parallel occurrence of catabolic and anabolic stimulation is complex, 124,156 and indeed paradoxical, as AMPK is a well‐established mTORC1 de‐activator 150,151 .…”

“…154 Perhaps to meet energy demand from this anabolic stimulation, 155 it is suggested by rodent pre-clinical studies that leucine also triggers an adaptive catabolic response that involves AMPK and that increases skeletal muscle mitochondrial biogenesis, mtDNA content, fatty acid oxidation and glucose uptake. 156 The apparently parallel occurrence of catabolic and anabolic stimulation is complex, 124,156 and indeed paradoxical, as AMPK is a well-established mTORC1 de-activator. 150,151 Leucine-induced catabolic and anabolic responses are thus likely separated temporally and spatially, through involvement of different fiber types.…”

Valine improves mitochondrial function and protects against oxidative stress

“…According to several studies (Hinkle et al. 2022 ), mitochondrial dysfunction is associated with oxidative stress, cellular damage and is thought to be a common underlying mechanism of metabolic diseases (Rocha et al. 2013 ; Walters et al.…”