GSK-3β negatively regulates skeletal myotube hypertrophy

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Abstract
To determine whether changes in glycogen synthase kinase-3β (GSK-3β) phosphorylation contribute to muscle hypertrophy, we delineated the effects of GSK-3β 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-3β. Application of IGF-I (250 ng/ml) or LiCl (10 mM) alone (i.e., both inhibit GSK-3β activity) increased the area of C2C12 myotubes by 80 and 85%, respectively. The application of IGF-I (250 ng/ml) elevated GSK-3β phosphorylation and reduced GSK-3β kinase activity by ∼800% and ∼25%, respectively. LY-294002 (100 μM) and wortmannin (150 μM), specific inhibitors of phosphatidylinositol 3′-kinase, attenuated IGF-I-induced GSK-3β phosphorylation by 67 and 92%, respectively. IGF-I suppressed the kinase activity of GSK-3β. 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-3β (cGSK-3β) inhibited the induction by IGF-I of NFAT-inducible reporter activity. LiCl, which inhibits GSK-3β, removed the block by cGSK-3β 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-3β.