Graça FA, Gonçalves DA, Silveira WA, Lira EC, Chaves VE, Zanon NM, Garófalo MA, Kettelhut IC, Navegantes LC. Epinephrine depletion exacerbates the fasting-induced protein breakdown in fast-twitch skeletal muscles. Am J Physiol Endocrinol Metab 305: E1483-E1494, 2013. First published October 22, 2013 doi:10.1152/ajpendo.00267.2013.-The physiological role of epinephrine in the regulation of skeletal muscle protein metabolism under fasting is unknown. We examined the effects of plasma epinephrine depletion, induced by adrenodemedullation (ADMX), on muscle protein metabolism in fed and 2-day-fasted rats. In fed rats, ADMX for 10 days reduced muscle mass, the cross-sectional area of extensor digitorum longus (EDL) muscle fibers, and the phosphorylation levels of Akt. In addition, ADMX led to a compensatory increase in muscle sympathetic activity, as estimated by the rate of norepinephrine turnover; this increase was accompanied by high rates of muscle protein synthesis. In fasted rats, ADMX exacerbated fasting-induced proteolysis in EDL but did not affect the low rates of protein synthesis. Accordingly, ADMX activated lysosomal proteolysis and further increased the activity of the ubiquitin (Ub)-proteasome system (UPS). Moreover, expression of the atrophy-related Ub ligases atrogin-1 and MuRF1 and the autophagy-related genes LC3b and GABARAPl1 were upregulated in EDL muscles from ADMXfasted rats compared with sham-fasted rats, and ADMX reduced cAMP levels and increased fasting-induced Akt dephosphorylation. Unlike that observed for EDL muscles, soleus muscle proteolysis and Akt phosphorylation levels were not affected by ADMX. In isolated EDL, epinephrine reduced the basal UPS activity and suppressed overall proteolysis and atrogin-1 and MuRF1 induction following fasting. These data suggest that epinephrine released from the adrenal medulla inhibits fasting-induced protein breakdown in fast-twitch skeletal muscles, and these antiproteolytic effects on the UPS and lysosomal system are apparently mediated through a cAMP-Aktdependent pathway, which suppresses ubiquitination and autophagy. epinephrine; fasting; muscle atrophy; protein degradation; cAMP ACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM (SNS) results in the targeted release of norepinephrine (NE) from peripheral nerve endings as well as the hormonal release of epinephrine from the adrenal medulla. The precise contribution of the neural and hormonal components to the regulation of catecholamine-dependent processes depends on the context and type of the stimulus (37). It is well established that sympathetic activity in different tissues is reduced by fasting, an effect that may contribute to a decrease in the metabolic rate under conditions of caloric restriction. Conversely, the adrenal medulla is stimulated or remains unaltered during fasting (50).Although this stimulation of epinephrine secretion is modest, it may contribute to substrate mobilization, particularly by facilitating the hydrolysis of triglycerides in adipose tissue and by aiding glycogenolysis i...