PI3 Kinase Regulation of Skeletal Muscle Hypertrophy and Atrophy

  • David J. GlassEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 346)


Activation of the PI3 kinase pathway can induce skeletal muscle hypertrophy, defined as an increase in skeletal muscle mass. In mammals, skeletal muscle hypertrophy occurs as a result of an increase in the size, as opposed to the number, of pre-existing skeletal muscle fibers. This pathway’s effects on skeletal muscle have been implicated most prominently downstream of Insulin-like growth factor 1 signaling. IGF-1’s pro-hypertrophy activity comes predominantly through its ability to activate the Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Akt is a serine-threonine protein kinase that can induce protein synthesis and block the transcriptional upregulation of key mediators of skeletal muscle atrophy, the E3 ubiquitin ligases MuRF1 and MAFbx (also called Atrogin-1), by phosphorylating and thereby inhibiting the nuclear translocation of the FOXO (also called “forkhead”) family of transcription factors. Once phosphorylated by Akt, the FOXOs are excluded from the nucleus, and upregulation of MuRF1 and MAFbx is blocked. MuRF1 and MAFbx mediate atrophy by ubiquitinating particular protein substrates, causing them to undergo degradation by the proteasome. MuRF1’s substrates include several components of the sarcomeric thick filament, including Myosin Heavy Chain (MyHC). Thus, by blocking MuRF1 activation, IGF-1 helps prevent the breakdown of the thick filament under atrophy conditions.

IGF1/PI3K/Akt signaling also can dominantly inhibit the effects of a secreted protein called “myostatin,” which is a member of the TGFβ family of proteins. Deletion or inhibition of myostatin causes an increase in skeletal muscle size, because myostatin acts both to inhibit myoblast differentiation and to block the Akt pathway. Thus by blocking myostatin, PI3K/Akt activation stimulates differentiation and protein synthesis by this distinct mechanism. Myostatin induces the phosphorylation and activation of the transcription factors of Smad2 and Smad3, downstream of the ActRII (Activin Receptor type II)/Alk (Activin Receptor-like kinase) receptor complex. Other TGFβ-like molecules can also block differentiation, including TGF-b1, GDF-11, activinA, BMP-2 and BMP-7. As mentioned, myostatin also downregulates the Akt/mTOR/p70S6 protein synthesis pathway, which mediates both differentiation in myoblasts and hypertrophy in myotubes. Blockade of the Akt/mTOR pathway, using siRNA to RAPTOR, a component of “TORC1” (TOR signaling Complex 1), increases myostatin-induced phosphorylation of Smad2; this establishes a “feed-forward mechanism,” because myostatin can downregulates TORC1, and this downregulation in turn amplifies myostatin signaling. Blockade of RAPTOR also facilitates myostatin’s inhibition of muscle differentiation. When added to post-differentiated myotubes, myostatin causes a decrease in their diameter – however, this does not happen through the normal “atrophy pathway.” Rather than causing upregulation of the E3 ubiquitin ligases MuRF1 and MAFbx, previously shown to mediate skeletal muscle atrophy, myostatin decreases expression of these atrophy markers in differentiated myotubes, as well as other genes normally upregulated during differentiation, such as MyoD and myogenin. These findings show that myostatin signaling acts by blocking genes induced during differentiation, even in a myotube, as opposed to activating the distinct “atrophy program.”


Skeletal Muscle Thick Filament Myoblast Differentiation Skeletal Muscle Atrophy FOXO Transcription Factor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Thanks to Drs. M. Fishman, B. Richardson, A. Mackenzie, as well as the rest of the Novartis Community, for their enthusiastic support and input. For this work, studies performed in large part by A.U. Trendelenburg, B. Clarke, and E. Latres, in particular, respectively, were referred.


  1. Bentzinger C, Romanino K, Cloëtta D, Lin S, Mascarenhas J, Oliveri F, Xia J, Casanova E, Costa C, Brink M et al (2008) Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab 8:411–424PubMedCrossRefGoogle Scholar
  2. Bhaskar PT, Hay N (2007) The two TORCs and Akt. Dev Cell 12:487–502PubMedCrossRefGoogle Scholar
  3. Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K et al (2001a) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294:1704–1708PubMedCrossRefGoogle Scholar
  4. Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ et al (2001b) Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 3:1014–1019PubMedCrossRefGoogle Scholar
  5. Bohni R, Riesgo-Escovar J, Oldham S, Brogiolo W, Stocker H, Andruss BF, Beckingham K, Hafen E (1999) Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. Cell 97:865–875PubMedCrossRefGoogle Scholar
  6. Borden KL, Freemont PS (1996) The RING finger domain: a recent example of a sequence-structure family. Curr Opin Struct Biol 6:396–401CrossRefGoogle Scholar
  7. Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM (1998) RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA 95:1432–1437PubMedCrossRefGoogle Scholar
  8. Centner T, Yano J, Kimura E, McElhinny AS, Pelin K, Witt CC, Bang ML, Trombitas K, Granzier H, Gregorio CC et al (2001) Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domain. J Mol Biol 306:717–726PubMedCrossRefGoogle Scholar
  9. Choi KM, McMahon LP, Lawrence JC Jr (2003) Two motifs in the translational repressor PHAS-I required for efficient phosphorylation by mTOR and recognition by raptor. J Biol Chem 278:19667–19673PubMedCrossRefGoogle Scholar
  10. Clarke BA, Drujan D, Willis MS, Murphy LO, Corpina RA, Burova E, Rakhilin SV, Stitt TN, Patterson C, Latres E et al (2007) The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle. Cell Metab 6:376–385PubMedCrossRefGoogle Scholar
  11. Cohen S, Brault JJ, Gygi SP, Glass DJ, Valenzuela DM, Gartner C, Latres E, Goldberg AL (2009) During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation. J Cell Biol 185:1083–1095PubMedCrossRefGoogle Scholar
  12. Coleman ME, DeMayo F, Yin KC, Lee HM, Geske R, Montgomery C, Schwartz RJ (1995) Myogenic vector expression of insulin-like growth factor I stimulates muscle cell differentiation and myofiber hypertrophy in transgenic mice. J Biol Chem 270:12109–12116PubMedCrossRefGoogle Scholar
  13. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789PubMedCrossRefGoogle Scholar
  14. Csibi A, Leibovitch M-P, Cornille K, Tintignac LA, Leibovitch SA (2009) MAFbx/Atrogin-1 controls the activity of the initiation factor eIF3-f in skeletal muscle atrophy by targeting multiple C-terminal lysines. J Biol Chem 284:4413–4421PubMedCrossRefGoogle Scholar
  15. Dehoux MJM, van Beneden RP, Fernandez-Celemin L, Lause PL, Thissen J-PM (2003) Induction of MafBx and Murf ubiquitin ligase mRNAs in rat skeletal muscle after LPS injection. FEBS Lett 544:214–217PubMedCrossRefGoogle Scholar
  16. Deruisseau KC, Kavazis AN, Deering MA, Falk DJ, Van Gammeren D, Yimlamai T, Ordway GA, Powers SK (2004) Mechanical ventilation induces alterations of the ubiquitin-proteasome pathway in the diaphragm. J Appl Physiol 98:1314–1321PubMedCrossRefGoogle Scholar
  17. DeVol DL, Rotwein P, Sadow JL, Novakofski J, Bechtel PJ (1990) Activation of insulin-like growth factor gene expression during work-induced skeletal muscle growth. Am J Physiol 259:E89–E95PubMedGoogle Scholar
  18. Du J, Mitch WE, Wang X, Price SR (2000) Glucocorticoids induce proteasome C3 subunit expression in L6 muscle cells by opposing the suppression of its transcription by NF-kappa B. J Biol Chem 275:19661–19666PubMedCrossRefGoogle Scholar
  19. Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL (2001) Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci U S A 98:14440–14445PubMedCrossRefGoogle Scholar
  20. Grobet L, Martin LJ, Poncelet D, Pirottin D, Brouwers B, Riquet J, Schoeberlein A, Dunner S, Menissier F, Massabanda J et al (1997) A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet 17:71–74PubMedCrossRefGoogle Scholar
  21. Hara K, Yonezawa K, Kozlowski MT, Sugimoto T, Andrabi K, Weng QP, Kasuga M, Nishimoto I, Avruch J (1997) Regulation of eIF-4E BP1 phosphorylation by mTOR. J Biol Chem 272:26457–26463PubMedCrossRefGoogle Scholar
  22. Hara K, Yonezawa K, Weng QP, 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 [published erratum appears in J Biol Chem 1998 Aug 21;273(34):22160]. J Biol Chem 273:14484–14494PubMedCrossRefGoogle Scholar
  23. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110:177–189PubMedCrossRefGoogle Scholar
  24. Hardt SE, Sadoshima J (2002) Glycogen synthase kinase-3beta: a novel regulator of cardiac hypertrophy and development. Circ Res 90:1055–1063PubMedCrossRefGoogle Scholar
  25. Hong DH, Forsberg NE (1995) Effects of dexamethasone on protein degradation and protease gene expression in rat L8 myotube cultures. Mol Cell Endocrinol 108:199–209PubMedCrossRefGoogle Scholar
  26. Izumiya Y, Hopkins T, Morris C, Sato K, Zeng L, Viereck J, Hamilton JA, Ouchi N, LeBrasseur NK, Walsh K (2008) Fast/glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell Metab 7:159–172PubMedCrossRefGoogle Scholar
  27. Jackson PK, Eldridge AG (2002) The SCF ubiquitin ligase: an extended look. Mol Cell 9:923–925PubMedCrossRefGoogle Scholar
  28. Kambadur R, Sharma M, Smith TP, Bass JJ (1997) Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle. Genome Res 7:910–916PubMedGoogle Scholar
  29. Kamei Y, Miura S, Suzuk M, Kai Y, Mizukami J, Taniguchi T, Mochida K, Hata T, Matsuda J, Aburatani H et al (2004) Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, down-regulated Type I (slow twitch/red muscle) fiber genes, and impaired glycemic control. J Biol Chem 279:41114–411123PubMedCrossRefGoogle Scholar
  30. Kamura T, Koepp DM, Conrad MN, Skowyra D, Moreland RJ, Iliopoulos O, Lane WS, Kaelin WG Jr, Elledge SJ, Conaway RC et al (1999) Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase [see comments]. Science 284:657–661PubMedCrossRefGoogle Scholar
  31. Kim do H, Sarbassov dos D, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110:163–175CrossRefGoogle Scholar
  32. Lagirand-Cantaloube J, Offner N, Csibi A, Leibovitch MP, Batonnet-Pichon S, Tintignac LA, Segura CT, Leibovitch SA (2008) The initiation factor eIF3-f is a major target for Atrogin1/MAFbx function in skeletal muscle atrophy. EMBO J 27:1266–1276PubMedCrossRefGoogle Scholar
  33. Lai K-MV, Gonzalez M, Poueymirou WT, Kline WO, Na E, Zlotchenko E, Stitt TN, Economides AN, Yancopoulos GD, Glass DJ (2004) Conditional activation of Akt in adult skeletal muscle induces rapid hypertrophy. Mol Cell Biol 24:9295–9304PubMedCrossRefGoogle Scholar
  34. Langley B, Thomas M, Bishop A, Sharma M, Gilmour S, Kambadur R (2002) Myostatin inhibits myoblast differentiation by down-regulating MyoD expression. J Biol Chem 277:49831–49840PubMedCrossRefGoogle Scholar
  35. Latres E, Amini AR, Amini AA, Griffiths J, Martin FJ, Wei Y, Lin HC, Yancopoulos GD, Glass DJ (2005) Insulin-like growth factor-1 (IGF-1) inversely regulates atrophy-induced genes via the phosphatidylinositol 3-kinase/akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. J Biol Chem 280:2737–2744PubMedCrossRefGoogle Scholar
  36. Lee S-J (2007) Quadrupling muscle mass in mice by targeting TGFbeta signaling pathways. PLoS One 2:e789PubMedCrossRefGoogle Scholar
  37. Lee SW, Dai G, Hu Z, Wang X, Du J, Mitch WE (2004) Regulation of muscle protein degradation: coordinated control of apoptotic and ubiquitin-proteasome systems by phosphatidylinositol 3 kinase. J Am Soc Nephrol 15:1537–1545PubMedCrossRefGoogle Scholar
  38. Leevers SJ, Weinkove D, MacDougall LK, Hafen E, Waterfield MD (1996) The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J 15:6584–6594PubMedGoogle Scholar
  39. Li H-H (2007) Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins. J Clin Invest 117:3211–3223PubMedCrossRefGoogle Scholar
  40. Li Y-P, Chen Y, Li AS, Reid MB (2003) Hydrogen peroxide stimulates ubiquitin conjugating activity and expression of genes for specific E2 and E3 proteins in skeletal muscle myotubes. Am J Physiol Cell Physiol 285:C806–C812PubMedGoogle Scholar
  41. Lorenz MC, Heitman J (1995) TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin. J Biol Chem 270:27531–27537PubMedCrossRefGoogle Scholar
  42. Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J et al (2007) FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6:458–471PubMedCrossRefGoogle Scholar
  43. McElhinny AS, Kakinuma K, Sorimachi H, Labeit S, Gregorio CC (2002) Muscle-specific RING finger-1 interacts with titin to regulate sarcomeric M-line and thick filament structure and may have nuclear functions via its interaction with glucocorticoid modulatory element binding protein-1. J Cell Biol 157:125–136PubMedCrossRefGoogle Scholar
  44. McFarlane C, Plummer E, Thomas M, Hennebry A, Ashby M, Ling N, Smith H, Sharma M, Kambadur R (2006) Myostatin induces cachexia by activating the ubiquitin proteolytic system through an NF-?B-independent, FoxO1-dependent mechanism. J Cell Physiol 209:501–514PubMedCrossRefGoogle Scholar
  45. McPherron AC, Lee SJ (1997) Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci U S A 94:12457–12461PubMedCrossRefGoogle Scholar
  46. McPherron AC, Lawler AM, Lee SJ (1997) Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 387:83–90PubMedCrossRefGoogle Scholar
  47. Montagne J, Stewart MJ, Stocker H, Hafen E, Kozma SC, Thomas G (1999) Drosophila S6 kinase: a regulator of cell size [see comments]. Science 285:2126–2129PubMedCrossRefGoogle Scholar
  48. Musaro A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M, Barton ER, Sweeney HL, Rosenthal N (2001) Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet 27:195–200PubMedCrossRefGoogle Scholar
  49. Pallafacchina G, Calabria E, Serrano AL, Kalhovde JM, Schiaffino S (2002) A protein kinase B-dependent and rapamycin- sensitive pathway controls skeletal muscle growth but not fiber type specification. Proc Natl Acad Sci U S A 25:25Google Scholar
  50. Pizon V, Iakovenko A, van der Ven PFM, Kelly R, Fatu C, Furst DO, Karsenti E, Gautel M (2002) Transient association of titin and myosin with microtubules in nascent myofibrils directed by the MURF2 RING-finger protein. J Cell Sci 115:4469–4482PubMedCrossRefGoogle Scholar
  51. Proud CG (2004) mTOR-mediated regulation of translation factors by amino acids. Biochem Biophys Res Commun 313:429–436PubMedCrossRefGoogle Scholar
  52. Rebbapragada A, Benchabane H, Wrana JL, Celeste AJ, Attisano L (2003) Myostatin signals through a transforming growth factor {beta}-like signaling pathway to block adipogenesis. Mol Cell Biol 23:7230–7242PubMedCrossRefGoogle Scholar
  53. Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S et al (2001) The tripartite motif family identifies cell compartments. EMBO J 20:2140–2151PubMedCrossRefGoogle Scholar
  54. Rios R, Fernandez-Nocelos S, Carneiro I, Arce VM, Devesa J (2004) Differential response to exogenous and endogenous myostatin in myoblasts suggests that myostatin acts as an autocrine factor in vivo. Endocrinology 145:2795–2803PubMedCrossRefGoogle Scholar
  55. Rommel C, Clarke BA, Zimmermann S, Nunez L, Rossman R, Reid K, Moelling K, Yancopoulos GD, Glass DJ (1999) Differentiation stage-specific inhibition of the raf-MEK-ERK pathway by Akt. Science 286:1738–1741PubMedCrossRefGoogle Scholar
  56. Rommel C, Bodine SC, Clarke BA, Rossman R, Nunez L, Stitt TN, Yancopoulos 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. Nat Cell Biol 3:1009–1013PubMedCrossRefGoogle Scholar
  57. Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT (1995) Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 270:815–822PubMedCrossRefGoogle Scholar
  58. Sacheck JM, Ohtsuka A, McLary SC, Goldberg AL (2004) IGF-1 stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin-ligases, atrogin-1 and MuRF1. Am J Physiol Endocrinol Metab 287:E591–E601PubMedCrossRefGoogle Scholar
  59. Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL (2004) Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117:399–412PubMedCrossRefGoogle Scholar
  60. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101PubMedCrossRefGoogle Scholar
  61. Saurin AJ, Borden KL, Boddy MN, Freemont PS (1996) Does this have a familiar RING? Trends Biochem Sci 21:208–214PubMedGoogle Scholar
  62. Schalm SS, Fingar DC, Sabatini DM, Blenis J (2003) TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol 13:797–806PubMedCrossRefGoogle Scholar
  63. Stitt TN, Drujan D, Clarke BA, Panaro FJ, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ (2004) The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 14:395–403PubMedCrossRefGoogle Scholar
  64. Sugita H, Kaneki M, Sugita M, Yasukawa T, Yasuhara S, Martyn JA (2005) Burn injury impairs insulin-stimulated Akt/PKB activation in skeletal muscle. Am J Physiol Endocrinol Metab 288:E585–E591PubMedCrossRefGoogle Scholar
  65. Tintignac LA, Lagirand J, Batonnet S, Sirri V, Leibovitch MP, Leibovitch SA (2005) Degradation of MyoD mediated by the SCF (MAFbx) ubiquitin ligase. J Biol Chem 280:2847–2856PubMedCrossRefGoogle Scholar
  66. Trendelenburg AU, Meyer A, Rohner D, Boyle J, Hatakeyama S, Glass DJ (2009) Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am J Physiol Cell Physiol 296:C1258–C1270PubMedCrossRefGoogle Scholar
  67. Tsuchida K, Nakatani M, Uezumi A, Murakami T, Cui X (2008) Signal transduction pathway through activin receptors as a therapeutic target of musculoskeletal diseases and cancer. Endocr J 55:11–21PubMedCrossRefGoogle Scholar
  68. van der Velden JLJ, Schols AMWJ, Willems J, Kelders MCJM, Langen RCJ (2008) Glycogen synthase kinase 3 suppresses myogenic differentiation through negative regulation of NFATc3. J Biol Chem 283:358–366PubMedCrossRefGoogle Scholar
  69. Vandenburgh HH, Karlisch P, Shansky J, Feldstein R (1991) Insulin and IGF-I induce pronounced hypertrophy of skeletal myofibers in tissue culture. Am J Physiol 260:C475–C484PubMedGoogle Scholar
  70. Vyas DR, Spangenburg EE, Abraha TW, Childs TE, Booth FW (2002) GSK-3beta negatively regulates skeletal myotube hypertrophy. Am J Physiol Cell Physiol 283:C545–C551PubMedGoogle Scholar
  71. Wang L, Luo GJ, Wang JJ, Hasselgren PO (1998) Dexamethasone stimulates proteasome- and calcium-dependent proteolysis in cultured L6 myotubes. Shock 10:298–306PubMedCrossRefGoogle Scholar
  72. Yan Z, Biggs RB, Booth FW (1993) Insulin-like growth factor immunoreactivity increases in muscle after acute eccentric contractions. J Appl Physiol 74:410–414PubMedGoogle Scholar
  73. Yang W, Zhang Y, Li Y, Wu Z, Zhu D (2007) Myostatin induces cyclin D1 degradation to cause cell cycle arrest through a phosphatidylinositol 3-kinase/AKT/GSK-3beta pathway and is antagonized by insulin-like growth factor 1. J Biol Chem 282:3799–3808PubMedCrossRefGoogle Scholar
  74. Zhang H, Stallock JP, Ng JC, Reinhard C, Neufeld TP (2000) Regulation of cellular growth by the drosophila target of rapamycin dTOR [In Process Citation]. Genes Dev 14:2712–2724PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Novartis Institute for Biomedical ResearchCambridgeUSA

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