Why Are Branched-Chain Amino Acids Increased in Starvation and Diabetes?

Abstract

Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are increased in starvation and diabetes mellitus. However, the pathogenesis has not been explained. It has been shown that BCAA catabolism occurs mostly in muscles due to high activity of BCAA aminotransferase, which converts BCAA and α-ketoglutarate (α-KG) to branched-chain keto acids (BCKAs) and glutamate. The loss of α-KG from the citric cycle (cataplerosis) is attenuated by glutamate conversion to α-KG in alanine aminotransferase and aspartate aminotransferase reactions, in which glycolysis is the main source of amino group acceptors, pyruvate and oxaloacetate. Irreversible oxidation of BCKA by BCKA dehydrogenase is sensitive to BCKA supply, and ratios of NADH to NAD+ and acyl-CoA to CoA-SH. It is hypothesized that decreased glycolysis and increased fatty acid oxidation, characteristic features of starvation and diabetes, cause in muscles alterations resulting in increased BCAA levels. The main alterations include (i) impaired BCAA transamination due to decreased supply of amino groups acceptors (α-KG, pyruvate, and oxaloacetate) and (ii) inhibitory influence of NADH and acyl-CoAs produced in fatty acid oxidation on citric cycle and BCKA dehydrogenase. The studies supporting the hypothesis and pros and cons of elevated BCAA concentrations are discussed in the article.

Lack of Increase in Muscle Mitochondrial Protein Synthesis During the Course of Aerobic Exercise and Its Recovery in the Fasting State Irrespective of Obesity

“…To our knowledge, there are no other reports contrasting acute effects of aerobic exercise on plasma amino acid concentrations between humans with and without obesity. It is possible that a physiological increase in amino catabolism and use of amino acids as source of fuel in muscle during exercise ( Wagenmakers, 1998 ; Overmyer et al, 2015 ) is less pronounced in the metabolic context of obesity, and where there is increased availability of fatty acids for oxidation ( Holecek, 2020 ). Alternatively, downregulation of the expression of amino acid-catabolizing enzymes in liver and adipose tissue in obesity can mediate a pathological circumstance that increases the concentration of amino acids in plasma in humans with obesity ( She et al, 2007 ; Wiklund et al, 2016 ), and which may counteract a physiological increase in amino acid catabolism in response to exercise in these individuals.…”

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

“…Similarly, BCAAs are increased fivefold in animals with type 1 diabetes mellitus (T1DM) ( Hutson and Harper, 1981 ; Aftring et al, 1988 ; Rodríguez et al, 1997 ), reviewed in Holeček (2020) . This could be due to the significant reduction in BCAT2 mRNA levels in skeletal muscle and liver of rabbits with T1DM induced by alloxan ( Gürke et al, 2015 ).…”

“…It is also possible that in insulin resistance, impairment in glucose metabolism may be linked to altered BCAA catabolism. Under such a condition, glycolysis is reduced, resulting in reduced pyruvate, and ultimately less TCA cycle flux and α-KG for transamination of BCAAs by BCAT2 ( Holeček, 2020 ). This leads to reduced BCAT2 activity in skeletal muscle, and increased BCAA levels in plasma.…”

Effect of the BCAT2 polymorphism (rs11548193) on plasma branched-chain amino acid concentrations after dietary intervention in subjects with obesity and insulin resistance

“…Moreover, in individuals with obesity, the increase in BCAAs has been associated with diverse metabolic alterations, mainly IR (3) . Nevertheless, IR could also cause the increase in BCAAs levels as has been previously reviewed (9,10) . In this regard, mitochondrial function plays a determinant role.…”