Exenatide Improves the Survival of Random-Pattern Skin Flap via TFE3 Mediated Autophagy Augment

Background: Random skin flaps are widely applied to rebuild and restore soft-tissue damage in reconstructive surgery. Nevertheless, severe ischemia and ischemia/reperfusion injury lead to flap necrosis, a major complication after operation occurring in reconstructive surgery. Exenatide exert therapeutic role in diabetic wounds, cardiac injury, and nonalcoholic fatty liver disease. However, whether Exenatide has a protective effect against flap necrosis remains unknown, and the underlying mechanism should be explored further. Methods: One hundred and forty-four mice were stochastically divided into the Control (n=30), Exe(n=30), Exe + 3 methyladenine (3MA) (n=24), Exe + chloroquine (CQ) (n=24), Exe + Scramble control (n=18), and Exe + TFE3 shRNA groups (n = 18). Flap tissues were obtained on postoperative day 7 to evaluate tissue vitality, angiogenesis, pyroptosis, oxidative stress, and autophagy using Immunohistochemistry, Immunofluorescence staining and western blotting. Findings: We found Exenatide increased the flap vitality, enhanced angiogenesis, reduced oxidative stress and alleviated pyroptosis and activate autophagy in random skin flap. Inhibition of autophagy by 3MA and CQ reversed the above effects of Exenatide in random skin flap, suggesting that autophagy exert a major role in pro-survival effect in skin flap. In mechanistic investigation, activation and nuclear translocation of TFE3 was found to mediate Exenatide – induced autophagy. Besides, nuclear translocation of TFE3 may result from activation of AMPK-SPK2-CARM1 and AMPK-mTOR signaling axis. Interpretation: Our findings revealed that Exenatide boosted the viability, enhanced angiogenesis, reduced oxidative stress, alleviated pyroptosis via upregulation of autophagy. These indicated that Exenatide is a potent autophagy enhancer and capable for promoting the viability of random skin flap, providing a promising novel therapeutic strategy. Funding Statement: Financial supports from Public Welfare Technology Research Project of Natural Science Foundation of China (No. 81601705 to Kailiang Zhou, No.81873942 to Weiyang Gao, No. 81801930 to Jian Ding, No. 81572227 and No. 81873992 to Huazi Xu); Zhejiang Provincial Medicine and Health Technology Project (No. 2017KY472 to Kailiang Zhou); Wenzhou Science and Technology Bureau Foundation (No.2016Y0350 to Jian Ding). Declaration of Interests: The author states that there is no conflict of interest. Ethics Approval Statement: Experimental steps involving animals strictly abided by the Guide for the Care and Use of Laboratory Animals of the China National Institutes of Health, which were approved of the Animal Care and Use Committee of Wenzhou Medical University (wydw2017–0022).