title: Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways.
abstract: Skeletal muscle is composed of multinucleated fibres, formed after the differentiation and fusion of myoblast precursors. Skeletal muscle atrophy and hypertrophy refer to changes in the diameter of these pre-existing muscle fibres. The prevention of atrophy would provide an obvious clinical benefit; insulin-like growth factor 1 (IGF-1) is a promising anti-atrophy agent because of its ability to promote hypertrophy. However, the signalling pathways by which IGF-1 promotes hypertrophy remain unclear, with roles suggested for both the calcineurin/NFAT (nuclear factor of activated T cells) pathway and the PtdIns-3-OH kinase (PI(3)K)/Akt pathway. Here we employ a battery of approaches to examine these pathways during the hypertrophic response of cultured myotubes to IGF-1. We report that Akt promotes hypertrophy by activating downstream signalling pathways previously implicated in activating protein synthesis: the pathways downstream of mammalian target of rapamycin (mTOR) and the pathway activated by phosphorylating and thereby inhibiting glycogen synthase kinase 3 (GSK3). In contrast, in addition to demonstrating that calcineurin does not mediate IGF-1-induced hypertrophy, we show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy.
authors.affiliation: Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591-6707, USA.
authors.forename: C
authors.initials: C
authors.lastname: Rommel
authors.forename: S C
authors.initials: SC
authors.lastname: Bodine
authors.forename: B A
authors.initials: BA
authors.lastname: Clarke
authors.forename: R
authors.initials: R
authors.lastname: Rossman
authors.forename: L
authors.initials: L
authors.lastname: Nunez
authors.forename: T N
authors.initials: TN
authors.lastname: Stitt
authors.forename: G D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: D J
authors.initials: DJ
authors.lastname: Glass
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002460:Cell Line; D039642:Eukaryotic Initiation Factors; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019703:Calcineurin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D039642:Eukaryotic Initiation Factors; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C499527:Eif4ebp1 protein, mouse; C546843:mTOR protein, mouse