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Dexamethasone Inhibits Insulin-Like Growth Factor Signaling and Potentiates Myoblast Apoptosis

Department of Neurology (J.R.S.), Howard Hughes Medical Institute (B.L.B.), and Huntsman Cancer Institute (A.T.), University of Utah Medical School, Salt Lake City, Utah 84132

Address all correspondence and requests for reprints to: J. Robinson Singleton, M.D., Department of Neurology, University of Utah Medical School, Room 3R-152, 50 North Medical Drive, Salt Lake City, Utah 84132. E-mail: rob.singleton{at}hsc.utah.edu

In the critically ill, glucocorticoids induce myopathy, combining profound protein catabolism and mild myotubular death. Insulin-like growth factors (IGFs) inhibit muscle catabolism through activation of phosphatidylinositol 3-kinase (PI3K). Using rat L6 myoblasts, we show that IGF-I also acts through PI3K to inhibit apoptosis induced by hyperosmolar metabolic stress with 300 mM mannitol. We find that the glucocorticoid dexamethasone inhibits this antiapoptotic effect of IGF-I by impairing PI3K signaling. Dexamethasone induces overexpression of the PI3K subunit p85, which, in turn, competes with the complete PI3K heterodimer for binding at insulin receptor substrate-1, inhibiting PI3K activation. Dexamethasone blocks IGF-I-induced phosphorylation of Akt, a PI3K-dependent process. Increased cellular p85 abundance, induced by either 10 µM dexamethasone or transient transfection with a plasmid coding for p85, significantly inhibits IGF-I rescue from apoptosis induced by mannitol, as indicated by both loss of cell viability and increased activity of caspase-3 by fluorogenic assay. Conversely, constitutively active PI3K inhibits death induced by mannitol, even in the presence of dexamethasone. These findings may have particular relevance in the pathogenesis of acute steroid myopathy in critical illness, in which catabolic glucocorticoid effects combine with acute metabolic stressors, including sepsis, fasting, and chemical denervation.

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