Asprosin attenuates diabetic cardiomyopathy through inhibiting autophagy mediated by AMPK/mTOR/ULK1 pathway

Aberrant Autophagy mediated by AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/unc-51 like kinase 1 (ULK1) pathway (a canonical Autophagy pathway) plays important roles in diabetic cardiomyopathy (DCM). Asprosin (ASP) secreted by white adipose tissue involves in systemic metabolism disorders. However, its role in DCM remains poorly understood. Therefore, the purpose of this study was to investigate its roles and underlying mechanisms in the DCM from the perspective of Autophagy and Apoptosis. In the in vivo experiments, we observed the effects of ASP deficiency (ASP^-/-) or ASP intervention on cardiac function, fibrosis, Autophagy, and Apoptosis in a diabetes mellitus (DM) mouse model induced by high-fat feeding and streptozotocin (STZ) injection; in the in vitro experiments, we evaluated the effects of ASP intervention with or without 3-methyladenine (3-MA) (Autophagy inhibitor) or siAMPK in a H9c2 model injured by high glucose (HG). Our results show that ASP intervention attenuates the myocardial injury induced by DM (P < 0.05) and HG (P < 0.05). In addition, the Autophagy level markedly increases (P < 0.05) in diabetic mice, and ASP deficiency worsens the increase induced by DM (P < 0.05). In contrast, ASP intervention alleviates overautophagy induced by DM (P < 0.05) or HG (P < 0.05). Mechanistically, the protective effect of ASP against myocardial injury is through inhibiting the overautophagy mediated by AMPK/mTOR/ULK1 pathway (P < 0.05). Taken together, the findings suggest that ASP would be a potential therapeutic target and the recombinant ASP might be a promising candidate to treat metabolism-associated CVD. Although the findings would present a promise for the treatment of DCM, it is worth noting that the mouse model used fails to fully mimic the human DCM pathophysiology.NEW & NOTEWORTHY We demonstrated for the first time that asprosin (ASP) has protective effects against diabetic cardiomyopathy. We found that ASP could stimulate the AMPK/mTOR/ULK1 pathway to reduce the level of Autophagy and Apoptosis of cardiomyocytes, thereby maintaining the normal physiological function of the heart.

apoptosis; asprosin; autophagy; diabetic cardiomyopathy; fibrosis.