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Effect of Orally Administered Branched-chain Amino Acids on Protein Synthesis and Degradation in Rat Skeletal Muscle
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 Title & Authors
Effect of Orally Administered Branched-chain Amino Acids on Protein Synthesis and Degradation in Rat Skeletal Muscle
Yoshizawa, Fumiaki; Nagasawa, Takashi; Sugahara, Kunio;
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Although amino acids are substrates for the synthesis of proteins and nitrogen-containing compounds, it has become more and more clear over the years that these nutrients are also extremely important as regulators of body protein turnover. The branched-chain amino acids (BCAAs) together or simply leucine alone stimulate protein synthesis and inhibit protein breakdown in skeletal muscle. However, it was only recently that the mechanism(s) involved in the regulation of protein turnover by BCAAs has begun to be defined. The acceleration of protein synthesis by these amino acids seems to occur at the level of peptide chain initiation. Oral administration of leucine to food-deprived rats enhances muscle protein synthesis, in part, through activation of the mRNA binding step of translation initiation. Despite our knowledge of the induction of protein synthesis by BCAAs, there are few studies on the suppression of protein degradation. The recent findings that oral administration of leucine rapidly reduced -methylhistidine (3-methylhistidine; MeHis) release from isolated muscle, an index of myofibrillar protein degradation, indicate that leucine suppresses myofiblilar protein degradation. The details of the molecular mechanism by which leucine inhibits proteolysis is just beginning to be elucidated. The purpose of this report was to review the current understanding of how BCAAs act as regulators of protein turnover.
Branched-chain amino acids;Protein synthesis;mRNA translation;Protein degradation;Skeletal muscle;Rats;
 Cited by
Alessi, D. R., M. Andjelkovic, B. Caudwell, P. Cron, N. Morrice, P. Cohen and B. A. Hemmings. 1996. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO. J. 15:6541-6551.

Anthony, J. C., T. G. Anthony and D. K. Layman. 1999. Leucine supplementation enhances skeletal muscle recovery in rats following exercise. J. Nutr. 129:1102-1106.

Anthony, J. C., T. G. Anthony, S. R. Kimball, T. C. Vary and L. S. Jefferson. 2000a. Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased eIF4F formation. J. Nutr. 130:139-145.

Anthony, J. C., F. Yoshizawa, T. G. Anthony, T. C. Vary, L. S. Jefferson and S. R. Kimball. 2000b. Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. J. Nutr. 130:2413-2419.

Anthony, J. C., C. H. Lang, S. J. Crozier, T. G. Anthony, D. A. MacLean, S. R. Kimball and L. S. Jefferson. 2002. Contribution of insulin to the translational control of protein synthesis in skeletal muscle by leucine. Am. J. Physiol. 282:E1092-E1101.

Busquets, S., B. Alvarez, M. Llovera, N. Agell, F. J. Lopez-Soriano and J. M. Argiles. 2000. Branched-chain amino acids inhibit proteolysis in rat skeletal muscle: mechanisms involved. J. Cell. Physiol. 184:380-384.

Carafoli, E. and M. Molinari. 1998. Calpain: a protease in search of a function? Biochem. Biophys. Res. Commun. 247:193-203.

Doherty, T. J. 2003. Aging and sarcopenia. J. Appl. Physiol. 95:1717-1727.

Fafournoux, P., A. Bruhat and C. Jousse. 2000. Amino acid regulation of gene expression. Biochem. J. 351:1-12.

Fox, H. L., P. T. Pham, S. R. Kimball, L. S. Jefferson and C. J. Lynch. 1998. Amino acid effects on translational repressor 4EBP1 are mediated primarily by L-leucine in isolated adipocytes. Am. J. Physiol. 275:C1232-1238.

Fulks, R. M., J. B. Li and A. L. Goldberg. 1975. Effects of insulin, glucose, and amino acids on protein turnover in rat diaphragm. J. Biol. Chem. 250:290-298.

Fumagalli, S. and G. Thomas. 2000. S6 phosphorylation and signal transduction. In Translational Control of Gene Expression. N. Sonenberg, (Ed. J. W. B. Hershey and M. B. Mathews). Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, pp. 695-717.

Garlick, P. J., M. A. McNurlan and V. R. Preedy. 1980. A rapid and convenient technique for measuring the rate of protein synthesis in tissues by injection of $[^3H]$ phenylalanine. Biochem. J. 192:719-723.

Goodman, M. N. and M. del Pilar Gomez. 1987. Decreased myofibrillar proteolysis after refeeding requires dietary protein or amino acids. Am. J. Physiol. 253:E52-E58.

Hamel, F. G., J. L. Upward, G. L. Siford and W. C. Duckworth. 2003. Inhibition of proteasome activity by selected amino acids. Metabolism. 52:810-814.

Hara, K., K. Yonezawa, Q. P. Weng, M. T. Kozlowski, C. Belham and J. Avruch. 1998. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem. 273:14484-14494.

Harris, C. I. and G. Milne. 1980. The urinary excretion of $N^\tau$-methylhistidine in sheep: an invalid index of muscle protein breakdown. Br. J. Nutr. 44:129-140.

Hershko, A. and A. Ciechanover. 1998. The ubiquitin system. Annu. Rev. Biochem. 67:425-479.

Hinnebusch, A. G. 2000. Mechanism and regulation of initiator methionyl-tRNA binding to ribosomes. In Translational Control of Gene Expression (Ed. N. Sonenberg, J. W. B. Hershey and M. B. Mathews). Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, pp. 185-243.

Huang, J. and N. E. Forsberg. 1998. Role of calpain in skeletalmuscle protein degradation. Proc. Natl. Acad. Sci. USA. 95:12100-12105.

Kadowaki, M. and T. Kanazawa. 2003. Amino acids as regulators of proteolysis. J. Nutr. 133:2052S-2056S.

Kanazawa, T., I. Taneike, R. Akaishi, F. Yoshizawa, N. Furuya, S Fujimura and M. Kadowaki. 2004. Amino acids and insulin control autophagic proteolysis through different signaling pathways in relation to mTOR in isolated rat hepatocytes. J. Biol. Chem. 279:8452-8459.

Lecker, S. H., V. Solomon, W. E. Mitch and A. L. Goldberg. 1999. Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states. J. Nutr. 129:227S-237S.

Louard, R. J., E. J. Barrett and R. A. Gelfand. 1990. Effect of infused branched-chain amino acids on muscle and wholebody amino acid metabolism in man. Clin. Sci. 79: 457-466.

Louard, R. J., E. J. Barrett and R. A. Gelfand. 1995. Overnight branched-chain amino acid infusion causes sustained suppression of muscle proteolysis. Metabolism. 44:424-429.

Malaisse, W. J. 1984. Branched chain amino and keto acids as regulators of insulin and glucagon release. In Branched Chain Amino and Keto Acids in Health and Disease (Ed. S. A. Adibi, W. Fekl, U. Langenbeck and P. Schauder). Karger, Basel, Switzerland, pp. 119-133.

Milne, G. and C. I. Harris. 1978. The inadequacy of urinary 3-methylhistidine excretion as an index of muscle protein degradations in the pig. Proc. Nutr. Soc. 37:18A.

Mordier, S., A. Bruchat, J. Averous and P. Fafournoux. 2002. Cellular adaptation to amino acid availability: mechanisms involved in the regulation of gene expression and protein metabolism. In Sensing, Signaling and Cell Adaptation (Ed. K. B. Storey and J. M. Storey). Elsevier Science B. V., Amsterdam, Holland, pp. 189-206.

Nagasawa, T. and R. Funabiki. 1981. Quantitative determination of urinary N-tau-methylhistidine output as an index of myofibrillar protein degradation. J. Biochem. 89:1155-1161.

Nagasawa, T., J. Hirano, F. Yoshizawa and N. Nishizawa. 1998. Myofibrillar protein catabolism is rapidly suppressed following protein feeding. Biosci. Biotechnol. Biochem. 62:1932-1937.

Nagasawa, T., T. Kido, F. Yoshizawa, Y. Ito and N. Nishizawa. 2002. Rapid suppression of protein degradation in skeletal muscle after oral feeding of leucine in rats. J. Nutr. Biochem. 13:121-127.

Nagasawa, T., N. Kikuchi, Y. Ito, F. Yoshizawa and N. Nishizawa. 2004. Suppression of myofibrillar protein degradation after refeeding in young and adult mice. J. Nutr. Sci. Vitaminol. (In press).

Nishizawa, N., T. Noguchi, S. Hareyama and R. Funabiki. 1977. Fractional flux rates of $N^\tau$-methylhistidine in skin and gastrointestine: the contribution of these tissues to urinary excretion of $N^\tau$-methylhistidine in the rat. Br. J. Nutr. 38:149-151.

Patti, M. E., E. Brambilla, L. Luzi, E. J. Landaker and C. R. Kahn. 1998. Bidirectional modulation of insulin action by amino acids. J. Clin. Invest. 101:1519-1529.

Pham, P. T., S. J. Heydrick, H. L. Fox, S. R. Kimball, L. S. Jefferson and C. J. Lynch. 2000. Assessment of cell-signaling pathways in the regulation of mammalian target of rapamycin (mTOR) by amino acids in rat adipocytes. J. Cell. Biochem. 79:427-441.

Ptushkina, M., T. von der Haar, M. M. Karim, J. M. Hughes and J. E. McCarthy. 1999. Repressor binding to a dorsal regulatory site traps human eIF4E in a high cap-affinity state. EMBO. J. 18:4068-4075.

Raught, B., A.-C. Gingras and N. Sonenberg. 2000. Regulation of ribosomal recruitment in eukaryotes. In Translational Control of Gene Expression (Ed. N. Sonenberg, J. W. B. Hershey and M. B. Mathews). Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, pp. 245-293.

Rooyackers, O. E. and K. S. Nair. 1997. Hormonal regulation of human muscle protein metabolism. Annu. Rev. Nutr. 17:457-485.

Schmelzle, T. and M. N. Hall. 2000. TOR, a central controller of cell growth. Cell. 103:253-262. crossref(new window)

Sekulic, A., C. C. Hudson, J. L. Homme, P. Yin, D. M. Otterness, L. M. Karnitz and R. T. Abraham. 2000. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogenstimulated and transformed cells. Cancer. Res. 60:3504-3513.

Tischler, M. E., M. Desautels and A. L. Goldberg. 1982. Does leucine, leucyl-tRNA, or some metabolite of leucine regulate protein synthesis and degradation in skeletal and cardiac muscle? J. Biol. Chem. 257:1613-1621.

van Sluijters, D. A., P. F. Dubbelhuis, E. F. Blommaart and A. J. Meijer. 2000. Amino-acid-dependent signal transduction. Biochem. J. 351:545-550.

Watt, P. W., M. E. Corbett and M. J. Rennie. 1992. Stimulation of protein synthesis in pig skeletal muscle by infusion of amino acids during constant insulin availability. Am. J. Physiol. 263:E453-E460.

Xu, G., G. Kwon, C. A. Marshall, T. A. Lin, J. C. Jr. Lawrence and M. L. McDaniel. 1998. Branched-chain amino acids are essential in the regulation of PHAS-I and p70 S6 kinase by pancreatic beta-cells. A possible role in protein translation and mitogenic signaling. J. Biol. Chem. 273:28178-28184.

Yoshizawa, F., S. R. Kimball and L. S. Jefferson. 1997. Modulation of translation initiation in rat skeletal muscle and liver in response to food intake. Biochem. Biophys. Res. Commun. 240:825-831.

Yoshizawa, F., S. R. Kimball, T. C. Vary and L. S. Jefferson. 1998. Effect of dietary protein on translation initiation in rat skeletal muscle and liver. Am. J. Physiol. 275:E814-E820.

Yoshizawa, F., S. Hirayama, H. Sekizawa, T. Nagasawa and K. Sugahara. 2002. Oral administration of leucine stimulates phosphorylation of 4E-BP1 and S6K1 in skeletal muscle but not in liver of diabetic rats. J. Nutr. Sci. Vitaminol. 48:59-64.

Yoshizawa, F., H. Sekizawa, S. Hirayama, Y. Yamazaki, T. Nagasawa and K. Sugahara. 2004. Tissu-specific regulation of 4E-BP1 and S6K1 phosphorylation by $\alpha$-ketoisocaproate. J. Nutr. Sci. Vitaminol. 50:56-60.

Young, V. R. and H. N. Munro. 1978. $N^\tau$-Methylhistidine (3-methylhistidine) and muscle protein turnover: an overview. Fed. Proc. 37:2291-2300.

Zanetti, M., R. Barazzoni, E. Kiwanuka and P. Tessari. 1999. Effects of branched-chain-enriched amino acids and insulin on forearm leucine kinetics. Clin. Sci. 97:437-448.