Skip to main content
×
×
Home

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

  • Douglas R. Bolster (a1), Leonard S. Jefferson (a1) and Scot R. Kimball
Abstract

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.

    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Regulation of protein synthesis associated with skeletal muscle hypertrophy by insulin-, amino acid- and exercise-induced signalling
      Available formats
      ×
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Regulation of protein synthesis associated with skeletal muscle hypertrophy by insulin-, amino acid- and exercise-induced signalling
      Available formats
      ×
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Regulation of protein synthesis associated with skeletal muscle hypertrophy by insulin-, amino acid- and exercise-induced signalling
      Available formats
      ×
Copyright
Corresponding author
* Corresponding author: Professor Scot R. Kimball Fax: +1 717 531 7667, Email: skimball@psu.edu
References
Hide All
Alessi, DR & Downes, CP (1998) The role of PI 3-kinase in insulin action. Biochimica et Biophysica Acta 1436, 151164.
Baar, K & Esser, KA (1999) Phosphorylation of p70 S6k correlates with increased skeletal muscle mass following resistance exercise. American Journal of Physiology 276, C120C127.
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.
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.
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.
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.
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.
Bolster, DR, Kimball, SR & Jefferson, LS (2003) Translational control mechanisms modulate skeletal muscle gene expression during hypertrophy. Exercise and Sport Sciences Reviews 31, 111116.
Cantley, LC (2002) The phosphoinositide 3-kinase pathway. Science 296, 16551657.
Coffer, PJ, Jin, J & Woodgett, JR (1998) Protein kinase B (c-Akt): a multifactorial mediator of phosphatidylinositol 3-kinase activation. Biochemical Journal 335, 113.
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.
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.
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.
Fluckey, JD, Kraemer, WJ & Farrell, PA (1995) Pancreatic islet insulin secretion is increased after resistance exercise in rats. Journal of Applied Physiology 79, 11001105.
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.
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.
Gingras, A-C Raught, B & Sonenberg, N (2001) Regulation of translation initiation by FRAP/mTOR. Genes and Development 15, 807826.
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.
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.
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.
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.
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.
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.
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.
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.
Meyuhas, O (2000) Synthesis of the translational apparatus is regulated at the translational level. European Journal of Biochemistry 267, 63216330.
Nader, GA & Esser, KA (2001) Intracellular signaling specificity in skeletal muscle in response to different modes of exercise. Journal of Applied Physiology 90, 19361942.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Proceedings of the Nutrition Society
  • ISSN: 0029-6651
  • EISSN: 1475-2719
  • URL: /core/journals/proceedings-of-the-nutrition-society
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed