GSK-3 negatively regulates skeletal myotube hypertrophy

Vyas, Dharmesh R., Espen E. Spangenburg, Tsghe W. Abraha, Thomas E. Childs, and Frank W. Booth. GSK-3 negatively regulates skeletal myotube hypertrophy. Am J Physiol Cell Physiol 283: C545–C551, 2002. First published April 3, 2002; 10.1152/ajpcell.00049.2002.—To determine whether changes in glycogen synthase kinase-3 (GSK-3 ) phosphorylation contribute to muscle hypertrophy, we delineated the effects of GSK-3 activity on C2C12 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-3 . Application of IGF-I (250 ng/ml) or LiCl (10 mM) alone (i.e., both inhibit GSK-3 activity) increased the area of C2C12 myotubes by 80 and 85%, respectively. The application of IGF-I (250 ng/ml) elevated GSK-3 phosphorylation and reduced GSK-3 kinase activity by 800% and 25%, respectively. LY-294002 (100 M) and wortmannin (150 M), specific inhibitors of phosphatidylinositol 3 -kinase, attenuated IGF-I-induced GSK-3 phosphorylation by 67 and 92%, respectively. IGF-I suppressed the kinase activity of GSK-3 . 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-3 (cGSK-3 ) inhibited the induction by IGF-I of NFAT-inducible reporter activity. LiCl, which inhibits GSK3 , removed the block by cGSK-3 on IGF-I-inducible NFATresponsive 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-3 .