title: GSK-3beta negatively regulates skeletal myotube hypertrophy.
abstract: To determine whether changes in glycogen synthase kinase-3beta (GSK-3beta) phosphorylation contribute to muscle hypertrophy, we delineated the effects of GSK-3beta activity on C(2)C(12) myotube size. We also examined possible insulin-like growth factor I (IGF-I) signaling of NFAT (nuclear factors of activated T cells)-inducible gene activity and possible modulation of NFAT activation by GSK-3beta. Application of IGF-I (250 ng/ml) or LiCl (10 mM) alone (i.e., both inhibit GSK-3beta activity) increased the area of C(2)C(12) myotubes by 80 and 85%, respectively. The application of IGF-I (250 ng/ml) elevated GSK-3beta phosphorylation and reduced GSK-3beta kinase activity by approximately 800% and approximately 25%, respectively. LY-294002 (100 microM) and wortmannin (150 microM), specific inhibitors of phosphatidylinositol 3'-kinase, attenuated IGF-I-induced GSK-3beta phosphorylation by 67 and 92%, respectively. IGF-I suppressed the kinase activity of GSK-3beta. IGF-I (250 ng/ml), but not LiCl (10 mM), induced an increase in NFAT-activated luciferase reporter activity. Cotransfection of a constitutively active GSK-3beta (cGSK-3beta) inhibited the induction by IGF-I of NFAT-inducible reporter activity. LiCl, which inhibits GSK-3beta, removed the block by cGSK-3beta on IGF-I-inducible NFAT-responsive reporter gene activity. These data suggest that the IGF-I-induced increase in skeletal myotube size is signaled, in part, through the inhibition of GSK-3beta.
authors.affiliation: Department of Veterinary Biomedical Sciences, and the Dalton Cardiovascular Institute, University of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Dharmesh R
authors.initials: DR
authors.lastname: Vyas
authors.forename: Espen E
authors.initials: EE
authors.lastname: Spangenburg
authors.forename: Tsghe W
authors.initials: TW
authors.lastname: Abraha
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Childs
authors.forename: Frank W
authors.initials: FW
authors.lastname: Booth
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D006984:Hypertrophy / Q000517:prevention & control; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000473:pathology*; D009135:Muscular Diseases / Q000517:prevention & control*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I; D038341:Glycogen Synthase Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride