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Akt Phosphorylation Is Not Sufficient for Insulin-Like Growth Factor-Stimulated Myogenin Expression but Must Be Accompanied by Down-Regulation of Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Phosphorylation

Department of Pediatrics (N.T., S.A., N.-Y.W., S.M.R.), University of California San Francisco, San Francisco, California 94143; and Cancer Research Institute (D.S.), University of California San Francisco, San Francisco, California 94115

Address all correspondence and requests for reprints to: Stephen M. Rosenthal, Department of Pediatrics, Box 0434, University of California San Francisco, San Francisco, California 94143-0434. E-mail: smr{at}itsa ucsf.edu.

IGF-I has a unique biphasic effect on skeletal muscle differentiation. Initially, IGF-I inhibits expression of myogenin, a skeletal muscle-specific regulatory factor essential for myogenesis. Subsequently, IGF-I switches to stimulating expression of myogenin. The mechanisms that mediate this switch in IGF action are incompletely understood. Several laboratories have demonstrated that the phosphatidylinositol-3-kinase/Akt signaling pathway is essential for myogenic differentiation and have suggested that this pathway mediates IGF-I stimulation of myogenin mRNA expression, an early critical step in the differentiation process. These studies, however, did not address concurrent Akt and MAPK/ERK1/2 phosphorylation, the latter of which is also known to regulate myogenic differentiation. In the present study in rat L6E9 muscle cells, we have manipulated ERK1/2 phosphorylation with either an upstream inhibitor or activator and examined concurrent levels of Akt and ERK1/2 phosphorylation and of myogenin mRNA expression in response to treatment with IGF-I. We find that even in the presence of phosphorylated Akt, it is only when ERK1/2 phosphorylation is inhibited that IGF-I can stimulate myogenin mRNA expression. Thus, although Akt phosphorylation may be necessary, it is not sufficient for induction of myogenic differentiation by IGF-I and must be accompanied by a decrease in ERK1/2 phosphorylation.

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