Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements

Abstract

Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids with protein anabolic properties, which have been studied in a number of muscle wasting disorders for more than 50 years. However, until today, there is no consensus regarding their therapeutic effectiveness. In the article is demonstrated that the crucial roles in BCAA metabolism play: (i) skeletal muscle as the initial site of BCAA catabolism accompanied with the release of alanine and glutamine to the blood; (ii) activity of branched-chain keto acid dehydrogenase (BCKD); and (iii) amination of branched-chain keto acids (BCKAs) to BCAAs. Enhanced consumption of BCAA for ammonia detoxification to glutamine in muscles is the cause of decreased BCAA levels in liver cirrhosis and urea cycle disorders. Increased BCKD activity is responsible for enhanced oxidation of BCAA in chronic renal failure, trauma, burn, sepsis, cancer, phenylbutyrate-treated subjects, and during exercise. Decreased BCKD activity is the main cause of increased BCAA levels and BCKAs in maple syrup urine disease, and plays a role in increased BCAA levels in diabetes type 2 and obesity. Increased BCAA concentrations during brief starvation and type 1 diabetes are explained by amination of BCKAs in visceral tissues and decreased uptake of BCAA by muscles. The studies indicate beneficial effects of BCAAs and BCKAs in therapy of chronic renal failure. New therapeutic strategies should be developed to enhance effectiveness and avoid adverse effects of BCAA on ammonia production in subjects with liver cirrhosis and urea cycle disorders. Further studies are needed to elucidate the effects of BCAA supplementation in burn, trauma, sepsis, cancer and exercise. Whether increased BCAA levels only markers are or also contribute to insulin resistance should be known before the decision is taken regarding their suitability in obese subjects and patients with type 2 diabetes. It is concluded that alterations in BCAA metabolism have been found common in a number of disease states and careful studies are needed to elucidate their therapeutic effectiveness in most indications.

Keywords: Ammonia; Cachexia; Cirrhosis; Diabetes; Glutamine; Nutrition.

Fig. 1

Main pathways of BCAA catabolism. ALA, alanine; GLU, glutamate; GLN, glutamine; HMB, β-hydroxy-β-methylbutyrate; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA; KIC, α-ketoisocaproate (ketoleucine); KIV, α-ketoisovalerate (ketovaline); KMV, α-keto-β-methylvalerate (ketoisoleucine); α-KG, α-ketoglutarate. 1, branched-chain-amino-acid aminotransferase (BCAT); 2, branched-chain α-keto acid dehydrogenase (BCKD); 3, KIC dioxygenase

Fig. 2

Cooperation of the muscles and the liver in BCAA catabolism. BCAA, branched-chain amino acids; BCKA, branched-chain keto acids

Fig. 3

The schemes of the BCAT reactions (BCAA deamination and BCKA amination) and supposed cycling of the BCAA and BCKA among organs, which may in various conditions attenuate the loss of essential BCAA [11]. ALA, alanine; BCAA, branched-chain amino acids; BCKA, branched-chain keto acids. GLU, glutamate; GLN, glutamine; PYR, pyruvate; α-KG, α-ketoglutarate

Fig. 4

Supposed effects of BCAA supplementation. ALA, alanine; BCAA, branched-chain amino acids; GLN, glutamine; ↑, increase; ↓, decrease

Fig. 5

Pathways of ammonia detoxification to GLN in muscles associated with enhanced consumption of the BCAA and α-KG (cataplerosis) and suggested effects of BCAA and phenylbutyrate in subjects with liver cirrhosis or UCD. Positive effect of BCAA on ammonia detoxification to GLN may be blunted by GLN degradation to ammonia in enterocytes and kidneys. Phenylbutyrate decreases ammonia via enhanced excretion of GLN by urine. An adverse side effect of phenylbutyrate is activation of BCKD resulting in the decrease of the BCAA. ALA, alanine; BCAA, branched-chain amino acids; BCKA, branched-chain keto acids. GLU, glutamate; GLN, glutamine; PYR, pyruvate; TCA cycle, tricarboxylic acid cycle; UCD, urea cycle disorders; α-KG, α-ketoglutarate. 1, branched-chain-amino-acid aminotransferase; 2, branched-chain α-keto acid dehydrogenase; 3, GLN synthetase

Fig. 6

Main alterations in protein and BCAA metabolism in disorders accompanied by SIRS. AA, amino acids; BCAA, branched-chain amino acids; BCKA, branched-chain keto acids; GLN, glutamine; SIRS, systemic inflammatory response syndrome; ↑, increase; ↓, decrease