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

Abstract

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 p85alpha, 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 p85alpha abundance, induced by either 10 microM dexamethasone or transient transfection with a plasmid coding for p85alpha, 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.

Mechanisms of glucocorticoid action in bone

“…The mechanism may involve suppression of IGF-I synthesis and signaling by glucocorticoids in myocytes since IGF-I increases protein synthesis and prevents proteolysis in muscle cells [40,41]. IGF-I suppresses the expression of the E3 ubiquitin ligand atrogin-1/ muscle atrophy F box (MAFbx), which activates protein degradation in the proteosome by ubiquitination [41].…”

Interplay between two myogenesis-related proteins: TBP-interacting protein 120B and MyoD

“…Insulin, one of the myogenesis inducers (Florini et al, 1996;Sacheck et al, 2004), also enhanced the expression of those genes (data not sown). Moreover, morphogenesis-blocking and muscle atrophy-inducing DEX (Singleton et al, 2000) reduced the expression of those factors at the mRNA level and/or protein level (Fig. 1B).…”

“…Expression of those genes was greatly increased when DM-maintained cells were treated with insulin as a physiological muscle-developing agent (data not shown) (Florini et al, 1996;Sacheck et al, 2004). We examined the effect of DEX, which inhibits myogenic signaling and causes muscle atrophy (Singleton et al, 2000), on the expression of those genes. Amounts of TIP120B and myogenin mRNAs were decreased by DEX, while MyoD mRNA was not greatly affected ( Fig.…”

Glucocorticoid-induced apoptosis and cellular mechanisms of myopathy

“…It has been consistently shown that glucocorticoids induce apoptosis in skeletal muscle as evidence by the activation of caspase-3, DNA fragmentation, and/or translocation of phosphatidylserine [7][8][9][10][11][12]. The signaling pathways responsible are slowly being unraveled.…”

“…IGF-I has an anabolic effect in skeletal muscle by increasing rate of protein synthesis [46] and by stimulating satellite cell proliferation and differentiation for growth and repair [47]. IGF-1 signaling plays an anti-catabolic role in skeletal muscle by suppressing the activity of the ubiquitin-proteasome system and also by suppressing apoptosis [12].…”