Neuregulin-4 attenuates diabetic cardiomyopathy by regulating autophagy via the AMPK/mTOR signalling pathway

Background: Diabetic cardiomyopathy is characterized by left ventricle dysfunction, cardiomyocyte Apoptosis, and interstitial fibrosis and is a serious complication of diabetes mellitus (DM). Autophagy is a mechanism that is essential for maintaining normal heart morphology and function, and its dysregulation can produce pathological effects on diabetic hearts. Neuregulin-4 (Nrg4) is an adipokine that exerts protective effects against metabolic disorders and Insulin resistance. The aim of this study was to explore whether Nrg4 could ameliorate DM-induced myocardial injury by regulating Autophagy.

Methods: Four weeks after the establishment of a model of type 1 diabetes in mice, the mice received Nrg4 treatment (with or without an Autophagy Inhibitor) for another 4 weeks. The cardiac functions, histological structures and cardiomyocyte Apoptosis were investigated. Autophagy-related protein levels along with related signalling pathways that regulate Autophagy were evaluated. In addition, the effects of Nrg4 on Autophagy were also determined in cultured primary cardiomyocytes.

Results: Nrg4 alleviated myocardial injury both in vivo and in vitro. The Autophagy level was decreased in type 1 diabetic mice, and Nrg4 intervention reactivated Autophagy. Furthermore, Nrg4 intervention was found to activate Autophagy via the AMPK/mTOR signalling pathway. Moreover, when Autophagy was suppressed or the AMPK/mTOR pathway was inhibited, the beneficial effects of Nrg4 were diminished.

Conclusion: Nrg4 intervention attenuated diabetic cardiomyopathy by promoting Autophagy in type 1 diabetic mice. Additionally, Nrg4 induced Autophagy via the AMPK/mTOR signalling pathway.

Autophagy; Diabetic cardiomyopathy; Neuregulin-4; Signalling pathway.