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Regulation of protein synthesis associated with skeletal muscle hypertrophy by insulin-, amino acid- and exercise-induced signalling

Published online by Cambridge University Press:  05 March 2007

Douglas R. Bolster
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, PO Box 850, Hershey, PA 17033, USA
Leonard S. Jefferson
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, PO Box 850, Hershey, PA 17033, USA
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Although insulin, amino acids and exercise individually activate multiple signal transduction pathways in skeletal muscle, one pathway, the phosphatidylinositol 3-kinase (PI3K)–mammalian target of rapamycin (mTOR) signalling pathway, is a target of all three. Activation of the PI3K–mTOR signal transduction pathway results in both acute (i.e. occurring in minutes to hours) and long-term (i.e. occurring in hours to days) up-regulation of protein synthesis through modulation of multiple steps involved in mediating the initiation of mRNA translation and ribosome biogenesis respectively. In addition, changes in gene expression through altered patterns of mRNA translation promote cell growth, which in turn promotes muscle hypertrophy. The focus of the present discussion is to review current knowledge concerning the mechanism(s) through which insulin, amino acids and resistance exercise act to activate the PI3K–mTOR signal transduction pathway and thereby enhance the rate of protein synthesis in muscle.

Symposium 5: Muscle hypertrophy: the signals of insulin, amino acids and exercise
Copyright © The Nutrition Society 2004


Alessi, DR & Downes, CP (1998) The role of PI 3-kinase in insulin action. Biochimica et Biophysica Acta 1436, 151164.CrossRefGoogle ScholarPubMed
Baar, K & Esser, KA (1999) Phosphorylation of p70 S6k correlates with increased skeletal muscle mass following resistance exercise. American Journal of Physiology 276, C120C127.Google ScholarPubMed
Biolo, G, Fleming, R & Wolfe, R (1995a) Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle. Journal of Clinical Investigation 95, 811819.CrossRefGoogle ScholarPubMed
Biolo, G, Maggi, S, Williams, B, Tipton, K & Wolfe, R, (1995b) Increased rates of muscle protein turnover and amino acid transport following resistance exercise in humans. American Journal of Physiology 268, E514E520.Google Scholar
Biolo, G, Tipton, KD, Klein, S & Wolfe, RR (1997) An abundant supply of amino acids enhances the metabolic effect of exercise on muscle protein. American Journal of Physiology 273, E122E129.Google ScholarPubMed
Biolo, G, Williams, BD, Fleming, RY & Wolfe, RR (1999) Insulin action on muscle protein kinetics and amino acid transport during recovery after resistance exercise. Diabetes 48, 949957.CrossRefGoogle ScholarPubMed
Bodine, SC, Stitt, TN, Gonzalez, M, Kline, WO, Stover, GL, Bauerlein, R, Zlotchenko, E, Scrimgeour, A, Lawrence, JC, Glass, DJ & Yancopoulous, GD (2001) Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nature Cell Biology 3, 10141019.CrossRefGoogle ScholarPubMed
Bolster, DR, Kimball, SR & Jefferson, LS (2003) Translational control mechanisms modulate skeletal muscle gene expression during hypertrophy. Exercise and Sport Sciences Reviews 31, 111116.CrossRefGoogle ScholarPubMed
Cantley, LC (2002) The phosphoinositide 3-kinase pathway. Science 296, 16551657.CrossRefGoogle ScholarPubMed
Coffer, PJ, Jin, J & Woodgett, JR (1998) Protein kinase B (c-Akt): a multifactorial mediator of phosphatidylinositol 3-kinase activation. Biochemical Journal 335, 113.CrossRefGoogle Scholar
Farrell, PA, Fedele, MJ, Vary, TC, Kimball, SR, Lang, CH & Jefferson, LS (1999) Regulation of protein synthesis after acute resistance exercise in diabetic rats. American Journal of Physiology 276, E721E727.Google ScholarPubMed
Fedele, MJ, Hernandez, JM, Lang, CH, Vary, TC, Kimball, SR, Jefferson, LS & Farrell, PA (2000) Severe diabetes prohibits elevations in muscle protein synthesis after acute resistance exercise in rats. Journal of Applied Physiology 88, 102108.Google ScholarPubMed
Fingar, DC, Salama, S, Tsou, C, Harlow, E & Blenis, J (2002) Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes and Development 16, 14721487.CrossRefGoogle ScholarPubMed
Fluckey, JD, Kraemer, WJ & Farrell, PA (1995) Pancreatic islet insulin secretion is increased after resistance exercise in rats. Journal of Applied Physiology 79, 11001105.Google ScholarPubMed
Gao, X, Zhang, Y, Arrazola, P, Hino, O, Kobayashi, T, Yeung, RS, Ru, B & Pan, D (2002) Tsc tumour suppressor proteins antagonize amino acid-mTOR signaling. Nature Cell Biology 4, 699704.CrossRefGoogle Scholar
Garami, A, Zwartkruis, FJT, Nobukuni, T, Joaquin, M, Roccio, M, Stocker, H, Kozma, SC, Hafen, E, Bos, JL & Thomas, G (2003) Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP1 signaling, is inhibited by TSC1 and 2. Molecular Cell 11, 14571466.CrossRefGoogle Scholar
Gingras, A-C Raught, B & Sonenberg, N (2001) Regulation of translation initiation by FRAP/mTOR. Genes and Development 15, 807826.CrossRefGoogle ScholarPubMed
Hara, K, Yonezawa, K, Weng, Q-P, Kozlowski, MT, Belham, C & Avruch, J (1998) Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. Journal of Biological Chemistry 273, 1448414494.CrossRefGoogle ScholarPubMed
Hernandez, JM, Fedele, MJ & Farrell, PA (2000) Time course evaluation of protein synthesis and glucose uptake after acute resistance exercise in rats. Journal of Applied Physiology 88, 11421149.Google ScholarPubMed
Hershey, JWB & Merrick, WC (2000) The pathway and mechanism of initiation of protein synthesis. In Translational Control of Gene Expression, pp. 3388. [Sonenberg, N, Hershey, JWB, and Mathews, MB, editors]. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.Google Scholar
Kim, D-H Sarbassov, DD, Ali, SM, Latek, RR, Guntur, KVP, Erdjument-Bromage, H, Tempst, P & Sabatini, D (2003) GβL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Molecular Cell 11, 895904.CrossRefGoogle ScholarPubMed
Kimball, SR, Farrell, PA & Jefferson, LS (2002) Role of insulin in translational control of protein synthesis in skeletal muscle by amino acids or exercise. Journal of Applied Physiology 93, 11681180.CrossRefGoogle ScholarPubMed
Kostyak, JC, Kimball, SR, Jefferson, LS & Farrell, PA (2001) Severe diabetes inhibits resistance exercise-induced increase in eukaryotic initiation factor 2B activity. Journal of Applied Physiology 91, 7984.Google ScholarPubMed
Kraemer, WJ, Volek, JS, Bush, JA, Putukian, M & Sebastianelli, WJ (1998) Hormonal responses to consecutive days of heavy-resistance exercise with or without nutritional supplementation. Journal of Applied Physiology 85, 15441555.Google ScholarPubMed
Manning, BD & Cantley, LC (2003) United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochemical Society Transactions 31, 573578.CrossRefGoogle ScholarPubMed
Meyuhas, O (2000) Synthesis of the translational apparatus is regulated at the translational level. European Journal of Biochemistry 267, 63216330.CrossRefGoogle ScholarPubMed
Nader, GA & Esser, KA (2001) Intracellular signaling specificity in skeletal muscle in response to different modes of exercise. Journal of Applied Physiology 90, 19361942.Google Scholar
Nave, BT, Ouwens, DM, Withers, DJ, Alessi, DR & Shepherd, PR (1999) Mammalian target of rapamycin is a direct target for protein kinase B: Identification of a convergence point for opposing effects of insulin and amino acid deficiency on protein translation. Biochemical Journal 344, 427431.CrossRefGoogle ScholarPubMed
Patti, M-E Brambilla, E, Luzi, L, Landaker, EJ & Kahn, CR (1998) Bidirectional modulation of insulin action by amino acids. Journal of Clinical Investigation 101, 15191529.CrossRefGoogle ScholarPubMed
Rasmussen, BB, Tipton, KD, Miller, SL, Wolf, SE & Wolfe, RR (2000) An oral essential amino acid-carbohydrate supplement enhances muscle protein anabolism after resistance exercise. Journal of Applied Physiology 88, 386392.Google ScholarPubMed
Reynolds, TH, Bodine, SC & Lawrence, JC (2002) Control of Ser 2448 phosphorylation in the mammalian target of rapamycin by insulin and skeletal muscle load. Journal of Biological Chemistry 277, 1765717662.CrossRefGoogle ScholarPubMed
Rommel, C, Bodine, SC, Clarke, BA, Rossman, R, Nunez, L, Stitt, TN, Yancopoulous, GD & Glass, DJ (2001) Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nature Cell Biology 3, 10091013.CrossRefGoogle ScholarPubMed
Sakamoto, K, Aschenbach, WG, Hirshman, MF & Goodyear, LJ (2003) Akt signaling in skeletal muscle: Regulation by exercise and passive stretch. American Journal of Physiology 285, E1081E1088.Google ScholarPubMed
Saucedo, LJ, Gao, X, Chiarelli, DA, Li, L, Pan, D & Edgar, BA (2003) Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nature Cell Biology 5, 566571.CrossRefGoogle ScholarPubMed
Tee, AR, Fingar, DC, Manning, BD, Kwiatkowski, DJ, Cantley, LC & Blenis, J (2002) Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proceedings of the National Academy of Sciences USA 99, 1357113576.CrossRefGoogle ScholarPubMed
Tipton, KD, Rasmussen, BB, Miller, SL, Wolf, SE, Owens-Stovall, SK, Petrini, BE & Wolfe, RR (2001) Timing of amino acid-carbohydrate ingestion alters anabolic response of muscle to resistance exercise. American Journal of Physiology 281, E197E206.Google ScholarPubMed
Welsh, GI, Miller, CM, Loughlin, AJ, Price, NT & Proud, CG (1998) Regulation of eukaryotic initiation factor eIF2B: glycogen synthase kinase-3 phosphorylates a conserved serine which undergoes dephosphorylation in response to insulin. FEBS Letters 421, 125130.CrossRefGoogle ScholarPubMed
Zhang, Y, Gao, X, Saucedo, LJ, Ru, B, Edgar, BA & Pan, D (2003) Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nature Cell Biology 5, 578581.CrossRefGoogle ScholarPubMed