RESUMO
ß2 -adrenoceptor agonists improve autophagy and re-establish proteostasis in cardiac cells; therefore, suggesting autophagy as a downstream effector of ß2 -adrenoceptor signaling pathway. Here, we used the pharmacological and genetic tools to determine the autophagy effect of sustained ß2 -adrenoceptor activation in rodents with neurogenic myopathy, which display impaired skeletal muscle autophagic flux. Sustained ß2 -adrenoceptor activation using Formoterol (10 µg kg-1 day-1 ), starting at the onset of neurogenic myopathy, prevents disruption of autophagic flux in skeletal muscle 14 days after sciatic nerve constriction. These changes are followed by reduction of the cytotoxic protein levels and increased skeletal muscle cross-sectional area and contractility properties. Of interest, sustained administration of Formoterol at lower concentration (1 µg kg-1 day-1 ) induces similar improvements in skeletal muscle autophagic flux and contractility properties in neurogenic myopathy, without affecting the cross-sectional area. Sustained pharmacological inhibition of autophagy using Chloroquine (50 mg kg-1 day-1 ) abolishes the beneficial effects of ß2 -adrenoceptor activation on the skeletal muscle proteostasis and contractility properties in neurogenic myopathy. Further supporting an autophagy mechanism for ß2 -adrenoceptor activation, skeletal muscle-specific deletion of ATG7 blunts the beneficial effects of ß2 -adrenoceptor on skeletal muscle proteostasis and contractility properties in neurogenic myopathy in mice. These findings suggest autophagy as a critical downstream effector of ß2 -adrenoceptor signaling pathway in skeletal muscle.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Autofagia , Músculo Esquelético/patologia , Doenças Musculares/prevenção & controle , Proteostase , Receptores Adrenérgicos beta 2/metabolismo , Animais , Fumarato de Formoterol , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contração Muscular , Músculo Esquelético/metabolismo , Doenças Musculares/etiologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta 2/química , Transdução de SinaisRESUMO
Increased proteolytic activity has been widely associated with skeletal muscle atrophy. However, elevated proteolysis is also critical for the maintenance of cellular homeostasis by disposing cytotoxic proteins and non-functioning organelles. We recently demonstrated that exercise activates autophagy and re-establishes proteostasis in cardiac diseases. Here, we characterized the impact of exercise on skeletal muscle autophagy and proteostasis in a model of neurogenic myopathy induced by sciatic nerve constriction in rats. Neurogenic myopathy, characterized by progressive atrophy and impaired contractility, was paralleled by accumulation of autophagy-related markers and loss of acute responsiveness to both colchicine and chloroquine. These changes were correlated with elevated levels of damaged proteins, chaperones and pro-apoptotic markers compared to control animals. Sustained autophagy inhibition using chloroquine in rats (50 mg.kg-1.day-1) or muscle-specific deletion of Atg7 in mice was sufficient to impair muscle contractility in control but not in neurogenic myopathy, suggesting that dysfunctional autophagy is critical in skeletal muscle pathophysiology. Finally, 4 weeks of aerobic exercise training (moderate treadmill running, 5x/week, 1 h/day) prior to neurogenic myopathy improved skeletal muscle autophagic flux and proteostasis. These changes were followed by spared muscle mass and better contractility properties. Taken together, our findings suggest the potential value of exercise in maintaining skeletal muscle proteostasis and slowing down the progression of neurogenic myopathy.