Alcohol intoxication impairs phosphorylation of S6K1 and S6 in skeletal muscle independently of ethanol metabolism

Background: The purpose of this study was to characterize the ability of alcohol to suppress insulin-like growth factor (IGF)-I stimulation of ribosomal S6 kinase 1 (S6K1) and 4E-BP1 phosphorylation, which are central elements in the signal transduction pathway used to coordinate the protein synthetic response and may contribute to the development of alcoholic myopathy. Methods: In vivo studies examined the dose and time dependency of the ability of alcohol to impair signal transduction under basal and IGF-I-stimulated conditions. Additional studies examined the effect of gender, nutritional state, and route of alcohol administration. A separate study determined the direct effects of alcohol on muscle metabolism by using the isolated perfused hindlimb preparation. Results: The phosphorylation of S6K1 and S6 in muscle was increased after injection of IGF-I in control rats. In contrast, IGF-I failed to stimulate S6K1 or S6 phosphorylation 2.5 hr after intraperitoneal administration of alcohol when the blood alcohol concentration was increased between ∼165 and 300 mg/dl. With a maximal suppressive dose of alcohol, the inhibitory effect on S6K1/S6 phosphorylation was observed as early as 1 hr and for up to 8 hr. The ability of alcohol to impair phosphorylation of S6K1 and S6 was independent of gender (male versus female), nutritional status (fed versus fasted), and route of alcohol administration (intraperitoneal versus oral). Furthermore, the suppressive effect of alcohol was still observed in rats pretreated with 4-methylpyrazole, suggesting that the response was independent of the oxidative metabolism of ethanol. The direct effect of alcohol on IGF-stimulated S6K1/S6 phosphorylation was also present when the isolated hindlimb was perfused in situ with buffer containing alcohol. In contrast to S6K1, acute alcohol intoxication did not consistently impair the ability of IGF-I to stimulate 4E-BP1 phosphorylation under any of the experimental conditions. Conclusions: These data indicate that acute alcohol intoxication selectively impairs IGF-I signaling via S6K1, but not 4E-BP1, and that this defect is independent of gender, nutritional state, route of administration, and alcohol metabolism. The IGF-I resistance may represent a participating mechanism by which alcohol directly limits the translation of selected messenger RNAs and, ultimately, protein synthesis in skeletal muscle.