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Early Stimulation and Late Inhibition of Extracellular Signal-Regulated Kinase 1/2 Phosphorylation by IGF-I: A Potential Mechanism Mediating the Switch in IGF-I Action on Skeletal Muscle Cell Differentiation

Department of Pediatrics, University of California, San Francisco, California 94143-0434

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

IGF-I has a unique biphasic effect on skeletal muscle cell differentiation. Initially, IGF-I inhibits differentiation and promotes proliferation of skeletal myoblasts. Subsequently, IGF-I switches to stimulating differentiation of these cells. The mechanisms responsible for this switch in IGF action remain unknown. We have examined the role of extracellular signal-regulated kinase (Erk)1/2 signaling in mediating the early inhibitory and late stimulatory effects of IGF-I on the gene expression of myogenin, a skeletal muscle-specific transcription factor essential for myogenic differentiation. We find that, concurrent with its early inhibitory and late stimulatory effects on myogenin mRNA, IGF-I has a biphasic but opposite effect on phosphorylation of Erk1/2: initially, IGF-I increases and subsequently decreases the phosphorylation of Erk1/2 in comparison to untreated cells. Cotreatment with an inhibitor of Erk1/2 activation prevents the early IGF-I-stimulation of Erk1/2 phosphorylation and partially reverses IGF-I-inhibition of myogenin mRNA. Conversely, preventing the late IGF-I-induced decrease in Erk1/2 phosphorylation blocks IGF-I-stimulation of myogenin mRNA. Our data indicate that the time-dependent, opposing effects of IGF-I on skeletal muscle cell differentiation are mediated, at least in part, by biphasic but opposite effects on activation of the Erk1/2 MAPK signaling pathway.

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