Epinephrine depletion exacerbates the fasting-induced protein breakdown in fast-twitch skeletal muscles

Abstract

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...

Formoterol decreases muscle wasting as well as inflammation in the rat model of rheumatoid arthritis

“…Similarly, ␤ 2 -adrenergic agonists have been reported to prevent cancerinduced muscle wasting and denervation-induced atrogin-1 and MuRF1 upregulation in muscle (3,12,19). Furthermore, chronic depletion of epinephrine exacerbates fasting-induced muscle proteolysis, increases atrogin-1, MuRF1, and LC3b expression and LC3b lipidation, and decreases p-Akt levels (20). The inhibitory effect of epinephrine on muscle proteolysis seems to be mediated by cAMP (50).…”

Higher insulin sensitivity in EDL muscle of rats fed a low-protein, high-carbohydrate diet inhibits the caspase-3 and ubiquitin-proteasome proteolytic systems but does not increase protein synthesis

“…Mizushima et al [24] showed that transgenic mice subjected to nutrient starvation experienced rapid and intense macroautophagy in the extensor digitorum longus (EDL) muscle, which almost exclusively contains fast-twitch fibers (glycolytic, type II), and experienced moderate and slow macroautophagy in the soleus muscles, which contains a high percentage of slow-twitch fibers (oxidative, type I). Furthermore, the regulation of extralysosomal proteolytic pathways can differ in skeletal muscles with different fiber-type compositions [25,26].…”

Interação funcional entre o sistema colinérgico e adrenérgico na manutenção da massa muscular e da placa motora

“…O tempo de 7 dias de desnervação motora foi selecionado pois neste momento o conteúdo dos atrogenes nos músculos desnervados está retornando aos valores normais e a atividade da via do AMPc/PKA está elevada. Embora trabalhos anteriores de nosso laboratório já tenham demonstrado que a ADMX é um procedimento eficaz na redução drástica da adrenalina circulante em ratos (GRAÇA et al, 2013;NAVEGANTES et al, 2001), não foi possível determinar a concentração plasmática desta catecolamina nos camundongos adrenodemedulados em virtude da alta quantidade de plasma exigida pelo método do CLAE. A concentração plasmática de corticosterona não foi afetada pela ADMX (Fig.…”