Potential antiproteolytic effects of L-leucine: observations of in vitro and in vivo studies

Nelo E Zanchi, Humberto Nicastro, Antonio H Lancha Jr, Nelo E Zanchi, Humberto Nicastro, Antonio H Lancha Jr

Abstract

The purpose of present review is to describe the effect of leucine supplementation on skeletal muscle proteolysis suppression in both in vivo and in vitro studies. Most studies, using in vitro methodology, incubated skeletal muscles with leucine with different doses and the results suggests that there is a dose-dependent effect. The same responses can be observed in in vivo studies. Importantly, the leucine effects on skeletal muscle protein synthesis are not always connected to the inhibition of skeletal muscle proteolysis. As a matter of fact, high doses of leucine incubation can promote suppression of muscle proteolysis without additional effects on protein synthesis, and low leucine doses improve skeletal muscle protein ynthesis but have no effect on skeletal muscle proteolysis. These research findings may have an important clinical relevancy, because muscle loss in atrophic states would be reversed by specific leucine supplementation doses. Additionally, it has been clearly demonstrated that leucine administration suppresses skeletal muscle proteolysis in various catabolic states. Thus, if protein metabolism changes during different atrophic conditions, it is not surprising that the leucine dose-effect relationship must also change, according to atrophy or pathological state and catabolism magnitude. In conclusion, leucine has a potential role on attenuate skeletal muscle proteolysis. Future studies will help to sharpen the leucine efficacy on skeletal muscle protein degradation during several atrophic states.

References

    1. Buse MG, Reid SS. Leucine: a possible regulator of protein turnover in muscle. J Clin Invest. 1975;56:1250–1261. doi: 10.1172/JCI108201.
    1. Tom A, Nair KS. Assessment of branched-chain amino Acid status and potential for biomarkers. J Nutr. 2006;136:324S–330S.
    1. Shimomura Y, Yamamoto Y, Bajotto G, Sato J, Murakami T, Shimomura N, Kobayashi H, Mawatari K. Nutraceutical effects of branched-chain amino acids in skeletal muscle. J Nutr. 2006;136:529S–532S.
    1. Tessari P, Inchiostro S, Biolo G, Trevisan R, Fantin G, Marescotti MC, Iori E, Tiengo A, Crepaldi G. Differential effects of hyperinsulinemia and hyperaminoacidemia on leucine-carbon metabolism in vivo. J Clin Invest. 1987;79:1062–1069. doi: 10.1172/JCI112919.
    1. Nair KS, Schwartz RG, Welle S. Leucine as a regulator of whole body and skeletal muscle protein metabolism in humans. Am J Physiol Endocrinol Metab. 1992;263:E928–E934.
    1. Louard RJ, Barret EJ, Gelfand RA. Overnight branched-chain amino acid infusion causes sustained suppression of muscle proteolysis. Metabolism. 1995;44:424–429. doi: 10.1016/0026-0495(95)90047-0.
    1. Kee AJ, Combaret L, Tilignac T, Souweine B, Aurousseau E, Dalle M, Taillandier D, Attaix D. Ubiquitin-proteasome-dependent muscle proteolysis responds slowly to insulin release and refeeding in starved rats. J Physiol. 2003;546:765–776. doi: 10.1113/jphysiol.2002.032367.
    1. Kobayashi H, Kato H, Hirabayashi Y, Murakami H, Suzuki H. Modulations of muscle protein metabolism by branched-chain amino acids in normal and muscle-atrophying rats. J Nutr. 2006;136:234S–236S.
    1. Tischler ME, Desautels M, Goldberg AL. Does leucine, leucyl-tRNA, or some metabolite of leucine regulate protein synthesis and degradation in skeletal and cardiac muscle? J Biol Chem. 1982;257:1613–1621.
    1. Mitch WE, Clark AS. Specificity of the effects of leucine and its metabolites on protein degradation in skeletal muscle. Biochem J. 1984;222:579–86.
    1. Busquets S, Alvarez B, Llovera M, Agell N, López-Soriano FJ, Argilés JM. Branched-chain amino acids inhibit proteolysis in rat skeletal muscle: mechanisms involved. J Cell Physiol. 2000;184:380–384. doi: 10.1002/1097-4652(200009)184:3<380::AID-JCP13>;2-F.
    1. Mitchell JC, Evenson AR, Tawa NE. Leucine inhibits proteolysis by the mTOR kinase signaling pathway in skeletal muscle. J Surg Res. 2004;121:311. doi: 10.1016/j.jss.2004.07.145.
    1. Nakashima K, Ishida A, Yamazaki M, Abe H. Leucine suppresses myofibrillar proteolysis by down-regulating ubiquitin-proteasome pathway in chick skeletal muscles. Bioch Biophys Res Commun. 2005;336:660–666. doi: 10.1016/j.bbrc.2005.08.138.
    1. Combaret L, Dardevet D, Rieu I, Pouch M, Béchet D, Taillander D, Grizard J, Attaix D. A leucine-supplemented diet restores the defective postprandial inhibition of proteasome-dependent proteolysis in aged rat skeletal muscle. J Physiol. 2005;569:489–499. doi: 10.1113/jphysiol.2005.098004.
    1. Mordier S, Deval C, Béchet D, Tassa A, Ferrara M. Leucine limitation induces autophagy and activation of lysosome-dependent proteolysis in C2C12 myotubes through a mammalian target of rapamycin-independent signaling pathway. J Biol Chem. 2000;275:29900–6. doi: 10.1074/jbc.M003633200.
    1. Ventrucci G, Mello MA, Gomes-Marcondes MC. Proteasome activity is altered in skeletal muscle tissue of tumour-bearing rats a leucine-rich diet. Endocr Relat Cancer. 2004;11:887–95. doi: 10.1677/erc.1.00828.
    1. Eley HL, Russell ST, Tisdale MJ. Effect of branched-chain amino acids on muscle atrophy in cancer cachexia. Biochem J. 2007;407:113–120. doi: 10.1042/BJ20070651.
    1. Sadiq F, Crompton LA, Scaife JR, Lomax MA. Effect of prolonged intravenous glucose and essential amino acid infusion on nitrogen balance, muscle protein degradation and ubiquitin-conjugating enzyme gene expression in calves. Nutr Metab (Lond) 2008;5:5. doi: 10.1186/1743-7075-5-5.
    1. Bohé J, Low A, Wolfe RR, Rennie MJ. Human muscle protein synthesis is modulated by extracellular, not intramuscular amino acid availability: a dose-response study. J Physiol. 2003;552:315–24. doi: 10.1113/jphysiol.2003.050674.
    1. Dardevet D, Sornet C, Balage M, Grizard J. Stimulation of in vitro rat muscle protein synthesis by leucine decreases with age. J Nutr. 2000;130:2630–2635.
    1. Divino Filho JC, Bergstrom J, Stehle P, Forst P. Simultaneous measurements of free amino acid patterns of plasma, muscle and erythrocytes in healthy human subjects. Clin Nutr. 1997;16:299–305. doi: 10.1016/S0261-5614(97)80015-5.
    1. Tassa A, Roux MP, Attaix D, Bechet DM. Class III phosphoinositide 3-kinase – Beclin1 complex mediates the amino acid-dependent regulation of autophagy in C2C12 myotubes. Biochem J. 2003;376:577–86. doi: 10.1042/BJ20030826.
    1. Mortimore GE, Khurana KK, Miotto G. Amino acid control of proteolysis in perfused livers of synchronously fed rats. Mechanism and specificity of alanine co-regulation. J Biol Chem. 1991;266:1021–8.
    1. Mortimore GE, Wert JJ, Jr, Miotto G, Venerando R, Kadowaki M. Leucine-specific binding of photoreactive Leu7-MAP to a high molecular weight protein on the plasma membrane of the isolated rat hepatocyte. Biochem Biophys Res Commun. 1994;203:200–8. doi: 10.1006/bbrc.1994.2168.
    1. Pösö AR, Wert JJ, Jr, Mortimore GE. Multifunctional control of amino acids of deprivation-induced proteolysis in liver. Role of leucine. J Biol Chem. 1982;257:12114–20.
    1. Buse MG, Weigand DA. Studies concerning the specificity of the effect of leucine on the turnover of proteins in muscles of control and diabetic rats. Biochim Biophys Acta. 1977;475:81–9.
    1. Hong SO, Layman DK. Effects of leucine on in vitro protein synthesis and degradation in rat skeletal muscles. J Nutr. 1984;114:1204–12.
    1. Goldspink DF, Garlick PJ, McNurlanti MA. Protein turnover measured in vivo and in vitro in muscles undergoing compensatory growth and subsequent denervation atrophy. Biochem J. 1983;210:89–98.
    1. Hasselgren PO, Pedersen P, Sax HC, Warner BW, Fischer JE. Methods for studying protein synthesis and degradation in liver and skeletal muscle. J Surg Res. 1988;45:389–415. doi: 10.1016/0022-4804(88)90136-9.
    1. Wassner SJ, Schlitzer JL, Li JB. A rapid, sensitive method for the determination of 3-methylhistidine levels in urine and plasma using high pressure liquid chromatography. Anal Biochem. 1980;104:284–289. doi: 10.1016/0003-2697(80)90076-7.
    1. Rennie MJ, Bennegård K, Edén E, Emery PW, Lundholm K. Urinary excretion and efflux from the leg of 3-methylhistidine before and after major surgical operation. Metabolism. 1984;33:250–6. doi: 10.1016/0026-0495(84)90046-5.
    1. Swick RW, Ip MM. Measurement of protein turnover in rat liver with (14C)carbonate. Protein turnover during liver regeneration. J Biol Chem. 1974;249:6836–41.
    1. Gelfand RA, Barrett EJ. Effect of physiologic hyperinsulinemia on skeletal muscle protein synthesis and breakdown in man. J Clin Invest. 1987;80:1–6. doi: 10.1172/JCI113033.
    1. Tessari P, Barazzoni R, Zanetti M. Differences in estimates of forearm protein synthesis between leucine and phenylalanine tracers following unbalanced amino acid infusion. Metabolism. 1999;48:1564–1569. doi: 10.1016/S0026-0495(99)90246-9.
    1. Katsanos CS, Chinkes DL, Sheffield-Moore M, Aarsland A, Kobayashi H, Wolfe RR. Method for the determination of the arteriovenous muscle protein balance during non-steady-state blood and muscle amino acid concentrations. Am J Physiol Endocrinol Metab. 2005;289:E1064–70. doi: 10.1152/ajpendo.00141.2005.
    1. Giordano M, Castellino P, DeFronzo RA. Differential responsiveness of protein synthesis and degradation to amino acid availability in humans. Diabetes. 1996;45:393–9. doi: 10.2337/diabetes.45.4.393.
    1. Sherwin RS. Effect of starvation on the turnover and metabolic response to leucine. J Clin Invest. 1978;61:1471–81. doi: 10.1172/JCI109067.
    1. Ferrando AA, Williams BD, Stuart CA, Lane HW, Wolfe RR. Oral branched-chain amino acids decrease whole-body proteolysis. J Parenter Enteral Nutr. 1995;19:47–54. doi: 10.1177/014860719501900147.
    1. Hoffer LJ, Taveroff A, Robitaille L, Hamadeh MJ, Mamer OA. Effects of leucine on whole body leucine, valine, and threonine metabolism in humans. Am J Physiol. 1997;272:E1037–42.
    1. Matthews DE. Observations of branched-chain amino acid administration in humans. J Nutr. 2005;135:1580S–1584S.
    1. Castellino P, Luzi L, Simonson DC, Haymond M, DeFronzo RA. Effect of insulin and plasma amino acid concentrations on leucine metabolism in man role of substrate availability on estimates of whole body protein synthesis. J Clin Invest. 1987;80:1784–1793. doi: 10.1172/JCI113272.
    1. Bohé J, Low JF, Wolfe RR, Rennie MJ. Latency and duration of stimulation of human muscle protein synthesis during continuous infusion of amino acids. J Physiol. 2001;532:575–579. doi: 10.1111/j.1469-7793.2001.0575f.x.
    1. Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A, Wolfe RR. A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly. Am J Physiol Endocrinol Metab. 2006;291:E381–7. doi: 10.1152/ajpendo.00488.2005.
    1. Yoshizawa F, Nagasawa T, Nishizawa N, Funabiki R. Protein synthesis and degradation change rapidly in response to food intake in muscle of food-deprived mice. J Nutr. 1997;127:1156–9.
    1. Nagasawa T, Kido T, Yoshizawa F, Ito Y, Nishizawa N. Rapid suppression of protein degradation in skeletal muscle after oral feeding of leucine in rats. J Nutr Biochem. 2002;13:121–127. doi: 10.1016/S0955-2863(01)00209-1.
    1. Pearlstein RA, Kohn RR. Myosin and total protein turnover in denervated rat skeletal muscle. Am J Pathol. 1966;48:823–9.
    1. Goldberg AL, Goodman HM. Effects of disuse and denervation on amino acid transport by skeletal muscle. Am J Physiol. 1969;216:1116–9.
    1. Paddon-Jones D, Sheffield-Moore M, Cree MG, Hewlings SJ, Aarsland A, Wolfe RR, Ferrando AA. Atrophy and impaired muscle protein synthesis during prolonged inactivity and stress. J Clin Endocrinol Metab. 2006;91:4836–41. doi: 10.1210/jc.2006-0651.
    1. Anello M, Ucciardello V, Piro S, Patané G, Frittitta L, Calabrese V, Giuffrida Stella AM, Vigneri R, Purrello F, Rabuazzo AM. Chronic exposure to high leucine impairs glucose-induced insulin release by lowering the ATP-to-ADP ratio. Am J Physiol Endocrinol Metab. 2001;281:E1082–7.

Source: PubMed

3
Abonneren