Amino acid availability rapidly regulates protein synthesis and degradation. Increasing amino acid concentrations above the levels found in post-absorptive plasma stimulates protein synthesis in a dose-dependent manner at the level of mRNA translation-initiation and inhibits protein degradation by inhibiting lysosomal autophagy. The anabolic effects of insulin on protein synthesis and protein degradation are exerted at the same sites (i.e., peptide chain initiation and lysosomal stabilization) allowing for a rapid synergistic response when both amino acids and insulin increase after a protein-containing meal. In perfused liver preparations, protein anabolic effects are exerted by a group of amino acids acting in concert. The BCAA are among the amino acids required for stimulation of hepatic protein synthesis, but there is no evidence that BCAA or leucine alone are effective. Leucine alone is an important inhibitor of hepatic protein degradation, but maximal inhibition requires in addition several other regulatory amino acids. In heart and skeletal muscle in vitro, increasing the concentration of the three BCAA or of leucine alone reproduces the effects of increasing the supply of all amino acids in stimulating protein synthesis and inhibiting protein degradation. Skeletal muscle is the largest repository of metabolically active protein and a major contributor to total body nitrogen balance. Supplying energy alone (i.e., carbohydrate and lipids) cannot prevent negative nitrogen balance (net protein catabolism) in animals or humans; only provision of amino acids allows the attainment of nitrogen balance. In rats and in humans nourished parenterally, provision of balanced amino acid solutions or of only the three BCAA cause similar improvements in nitrogen balance for several days. There is some evidence that infusions of leucine alone can stimulate muscle protein synthesis in vivo; the effect may be transitory and was not observed by all investigators; provisions of excess leucine alone does not seem to affect total body or muscle protein degradation in vivo. In postabsorptive rats, in vivo, infusion of the three BCAA together stimulates muscle protein synthesis as much as the infusion of a complete amino acid mixture or of a mixture of essential amino acids; the in vivo effect requires coinfusion of glucose or of small (physiological) doses of insulin, suggesting synergism between insulin and amino acids.(ABSTRACT TRUNCATED AT 400 WORDS)