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GROWTH, DIFFERENTIATION, AND APOPTOSIS

Inhibition of glycogen synthase kinase-3 activity is sufficient to stimulate myogenic differentiation

¹Department of Respiratory Medicine, Maastricht University, Maastricht, The Netherlands; and ²Department of Pathology, University of Vermont, Burlington, Vermont

Submitted 16 February 2005 ; accepted in final form 8 September 2005

Skeletal muscle atrophy is a prominent and disabling feature of chronic wasting diseases. Prevention or reversal of muscle atrophy by administration of skeletal muscle growth (hypertrophy)-stimulating agents such as insulin-like growth factor I (IGF-I) could be an important therapeutic strategy in these diseases. To elucidate the IGF-I signal transduction responsible for muscle formation (myogenesis) during muscle growth and regeneration, we applied IGF-I to differentiating C₂C₁₂ myoblasts and evaluated the effects on phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase-3 (GSK-3) signaling and myogenesis. IGF-I caused phosphorylation and inactivation of GSK-3 activity via signaling through the PI3K/Akt pathway. We assessed whether pharmacological inhibition of GSK-3 with lithium chloride (LiCl) was sufficient to stimulate myogenesis. Addition of IGF-I or LiCl stimulated myogenesis, evidenced by increased myotube formation, muscle creatine kinase (MCK) activity, and troponin I (TnI) promoter transactivation during differentiation. Moreover, mRNAs encoding MyoD, Myf-5, myogenin, TnI-slow, TnI-fast, MCK, and myoglobin were upregulated in myoblasts differentiated in the presence of IGF-I or LiCl. Importantly, blockade of GSK-3 inhibition abrogated IGF-I- but not LiCl-dependent stimulation of myogenic mRNA accumulation, suggesting that the promyogenic effects of IGF-I require GSK-3 inactivation and revealing an important negative regulatory role for GSK-3 in myogenesis. Therefore, this study identifies GSK-3 as a potential target for pharmacological stimulation of muscle growth.

insulin-like growth factor I; muscle hypertrophy

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				J. L. J. van der Velden, R. C. J. Langen, M. C. J. M. Kelders, J. Willems, E. F. M. Wouters, Y. M. W. Janssen-Heininger, and A. M. W. J. Schols Myogenic differentiation during regrowth of atrophied skeletal muscle is associated with inactivation of GSK-3beta Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1636 - C1644. [Abstract] [Full Text] [PDF]