Dexamethasone inhibits insulin-like growth factor signaling and potentiates myoblast apoptosis

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 throu gh PI3K to inhibit apoptosis induced by hyperosmolar metabolic stress with 300 mM mannitol. We find that the glucocorticoid dexamethasone inhibits thi s antiapoptotic effect of IGF-I by impairing PI3K signaling. Dexamethasone induces overexpression of the PI3K subunit p85 alpha, which, in turn, compe tes with the complete PI3K heterodimer for binding at insulin receptor subs trate-1, inhibiting PI3K activation. Dexamethasone blocks IGF-I-induced pho sphorylation of Akt, a PI3K-dependent process. Increased cellular p85a abun dance, induced by either 10 mu M dexamethasone or transient transfection wi th a plasmid coding for p85 alpha, 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, cons titutively active PI3K inhibits death induced by mannitol, even in the pres ence of dexamethasone. These findings may have particular relevance in the pathogenesis of acute steroid myopathy in critical illness, in which catabo lic glucocorticoid effects combine with acute metabolic stressors, includin g sepsis, fasting, and chemical denervation.