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

被引:73
作者
Singleton, JR
Baker, BL
Thorburn, A
机构
[1] Univ Utah, Sch Med, Dept Neurol, Salt Lake City, UT 84132 USA
[2] Univ Utah, Sch Med, Howard Hughes Med Inst, Salt Lake City, UT 84132 USA
[3] Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84132 USA
关键词
D O I
10.1210/en.141.8.2945
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 alpha, 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 p85a abundance, induced by either 10 mu M dexamethasone or transient transfection with 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, 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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页码:2945 / 2950
页数:6
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