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Metformin Promotes the Survival of Random-Pattern Skin Flaps by Inducing Autophagy Via the AMPK-mTOR-TFEB Signaling Pathway
42 Pages Posted: 5 Sep 2018
More...Abstract
Random-pattern skin flaps are widely used to close defects in reconstructive and plastic surgeries; however, they are vulnerable to necrosis, particularly in the distal portion of the flap. Here, we examined the effects of metformin on flap survival and the mechanisms underlying these effects. Following metformin treatment, the survival area, blood flow, and number of microvessels present in skin flaps were increased on postoperative day 7, whereas tissue edema was reduced. In addition, metformin promoted angiogenesis, inhibited apoptosis, relieved oxidative stress, and increased autophagy in areas of ischemia; these effects were reversed by an autophagy inhibitor, 3-methyladenine. 3-methyladenine also reversed the metformin-induced increase in flap viability. Similarly, treatment with an AMPK inhibitor, Compound C, inhibited metformin-induced autophagy by downregulating the AMPK-mTOR-TFEB signaling pathway. Taken together, our findings suggest that metformin enhances the survival of random-pattern skin flaps by enhancing angiogenesis and suppressing apoptosis and oxidative stress. These effects result from increased autophagy mediated by activation of the AMPK-mTOR-TFEB signaling pathway.
Funding Statement: This work was supported by grants from Natural Science Foundation of China (No. 81601705 to Kailiang Zhou, No. 81572227 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, No. 2015Y 0060 to Shi Li); Zhejiang Provincial Medicine and Health Platform Project (No. 2014ZDA015 Weiyang Gao).
Declaration of Interests: There are no conflicts of interest.
Ethics Approval Statement: The animal operation and treatment conformed to the Guide for the Care and Use of Laboratory Animals of China National Institutes of Health. All animal experiments were approved by the Animal Research Committee of Wenzhou Medical University (wydw2017–0022).
Keywords: Random-Pattern Skin Flaps; Metformin; Autophagy; AMPK-mTOR-TFEB Signaling Pathway
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