Metformin Promotes the Survival of Random-Pattern Skin Flaps by Inducing Autophagy via the AMPK-mTOR-TFEB signaling pathway

Wu, Hongqiang; Ding, Jian; Li, Shihen; Lin, Jinti; Jiang, Renhao; Lin, Chen; Dai, Li; Xie, Chenglong; Lin, Dingsheng; Xu, Huazi; Gao, Weiyang; Zhou, Kailiang

doi:10.7150/ijbs.29009

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Int J Biol Sci 2019; 15(2):325-340. doi:10.7150/ijbs.29009 This issue Cite

Research Paper

Metformin Promotes the Survival of Random-Pattern Skin Flaps by Inducing Autophagy via the AMPK-mTOR-TFEB signaling pathway

Hongqiang Wu^1,2,3*, Jian Ding^1,2,3*, Shihen Li^1,2,3, Jinti Lin^1,2,3, Renhao Jiang^1,2,3, Chen Lin^1,2,3, Li Dai^1,2,3, Chenglong Xie^1,2,3, Dingsheng Lin^1,2,3, Huazi Xu^1,2,3, Weiyang Gao^1,2,3✉, Kailiang Zhou^1,2,3✉

1. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
2. Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China
3. The Second Clinical Medical College of Wenzhou Medical University, Wenzhou 325027, China
*These authors contributed equally to this work.

✉ Corresponding authors: Prof. Weiyang Gao, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109 West Xueyuan Road, Wenzhou 325000, Zhejiang, China; Tel: +86-577-88002812; E-mail: More

Citation:

Wu H, Ding J, Li S, Lin J, Jiang R, Lin C, Dai L, Xie C, Lin D, Xu H, Gao W, Zhou K. Metformin Promotes the Survival of Random-Pattern Skin Flaps by Inducing Autophagy via the AMPK-mTOR-TFEB signaling pathway. Int J Biol Sci 2019; 15(2):325-340. doi:10.7150/ijbs.29009. https://www.ijbs.com/v15p0325.htm

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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 autophagy inhibitors 3-methyladenine (3MA) or chloroquine (CQ). Either 3MA or CQ reversed the metformin-induced increase in flap viability. Moreover, metformin also activated the AMPK-mTOR-TFEB signaling pathway in ischemic areas. Inhibitions of AMPK via Compound C (CC) or AMPK shRNA adeno-associated virus (AAV) vector resulted in the downregulation of the AMPK-mTOR-TFEB signaling pathway and autophagy level in metformin-treated flaps. Taken together, our findings suggest that metformin improves 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.

Keywords: Random-pattern skin flaps, Metformin, Autophagy, AMPK-mTOR-TFEB signaling pathway

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APA

Wu, H., Ding, J., Li, S., Lin, J., Jiang, R., Lin, C., Dai, L., Xie, C., Lin, D., Xu, H., Gao, W., Zhou, K. (2019). Metformin Promotes the Survival of Random-Pattern Skin Flaps by Inducing Autophagy via the AMPK-mTOR-TFEB signaling pathway. International Journal of Biological Sciences, 15(2), 325-340. https://doi.org/10.7150/ijbs.29009.

ACS

Wu, H.; Ding, J.; Li, S.; Lin, J.; Jiang, R.; Lin, C.; Dai, L.; Xie, C.; Lin, D.; Xu, H.; Gao, W.; Zhou, K. Metformin Promotes the Survival of Random-Pattern Skin Flaps by Inducing Autophagy via the AMPK-mTOR-TFEB signaling pathway. Int. J. Biol. Sci. 2019, 15 (2), 325-340. DOI: 10.7150/ijbs.29009.

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CSE

Wu H, Ding J, Li S, Lin J, Jiang R, Lin C, Dai L, Xie C, Lin D, Xu H, Gao W, Zhou K. 2019. Metformin Promotes the Survival of Random-Pattern Skin Flaps by Inducing Autophagy via the AMPK-mTOR-TFEB signaling pathway. Int J Biol Sci. 15(2):325-340.

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