title: Epinephrine depletion exacerbates the fasting-induced protein breakdown in fast-twitch skeletal muscles.
abstract: 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 ADMX-fasted 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-Akt-dependent pathway, which suppresses ubiquitination and autophagy.
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil;
authors.forename: Flávia A
authors.initials: FA
authors.lastname: Graça
authors.forename: Dawit A P
authors.initials: DA
authors.lastname: Gonçalves
authors.forename: Wilian A
authors.initials: WA
authors.lastname: Silveira
authors.forename: Eduardo C
authors.initials: EC
authors.lastname: Lira
authors.forename: Valéria Ernestânia
authors.initials: VE
authors.lastname: Chaves
authors.forename: Neusa M
authors.initials: NM
authors.lastname: Zanon
authors.forename: Maria Antonieta R
authors.initials: MA
authors.lastname: Garófalo
authors.forename: Isis C
authors.initials: IC
authors.lastname: Kettelhut
authors.forename: Luiz C C
authors.initials: LC
authors.lastname: Navegantes
mesh_terms: D000273:Adipose Tissue / Q000033:anatomy & histology / Q000187:drug effects; D000313:Adrenal Medulla / Q000502:physiology / Q000601:surgery; D000818:Animals; D001823:Body Composition / Q000187:drug effects / Q000502:physiology; D002395:Catecholamines / Q000097:blood; D004837:Epinephrine / Q000172:deficiency* / Q000494:pharmacology; D005215:Fasting / Q000378:metabolism*; D008297:Male; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism*; D009638:Norepinephrine / Q000097:blood; D009929:Organ Size / Q000187:drug effects; D059748:Proteolysis; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002395:Catecholamines; D009638:Norepinephrine; D004837:Epinephrine
keywords: cAMP; epinephrine; fasting; muscle atrophy; protein degradation