Acute attenuation of translation initiation and protein synthesis by glucocorticoids in skeletal muscle

Glucocorticoids are diabetogenic factors that not only antagonize the actio n of insulin in target tissues but also render these tissues catabolic. The refore, in rats, we endeavored to characterize the effects in skeletal musc le of glucocorticoids on translation initiation, a regulated process that, in part, governs overall protein synthesis through the modulated activities of eukaryotic initiation factors (eIFs). Four hours after intraperitoneal administration of dexamethasone (100 mu g/100 g body wt), protein synthesis in skeletal muscle was reduced to 59% of the value recorded in untreated c ontrol animals. Furthermore, translation initiation factor eIF4E preferred association with its endogenous inhibitor 4E-BP1 rather than eIF4G. Dexamet hasone treatment resulted in dephosphorylation of both 4E-BP1 and the 40S r ibosomal protein S6 kinase concomitant with enhanced phosphorylation of eIF 4E. Moreover, the guanine nucleotide exchange activity of eIF2B was unaffec ted as was phosphorylation of the alpha-subunit of eIF2. Hence glucocortico ids negatively modulate the activation of a subset of the protein synthetic machinery, thereby contributing to the catabolic properties of this class of hormones in vivo.