2. Academic Validation
  3. FGF21 augments autophagy in random-pattern skin flaps via AMPK signaling pathways and improves tissue survival

FGF21 augments autophagy in random-pattern skin flaps via AMPK signaling pathways and improves tissue survival

  • Cell Death Dis. 2019 Nov 18;10(12):872. doi: 10.1038/s41419-019-2105-0.
Kailiang Zhou 1 2,  Huanwen Chen 3,  Jinti Lin 1 2,  Hui Xu 1 2,  Hongqiang Wu 1 2,  Guodong Bao 1 2,  Jiafeng Li 1 2,  Xiangyang Deng 4,  Xiaolong Shui 1 2,  Weiyang Gao 1 2,  Jian Ding 5 6,  Jian Xiao 7,  Huazi Xu 8 9
Affiliations

Affiliations

  • 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 University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
  • 4 Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
  • 5 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China. dingdingdang9770@163.com.
  • 6 Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China. dingdingdang9770@163.com.
  • 7 Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325027, China. xfxj2000@126.com.
  • 8 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China. 269372562@qq.com.
  • 9 Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China. 269372562@qq.com.
PMID: 31740658 DOI: 10.1038/s41419-019-2105-0
Abstract

Random-pattern skin FLAP is commonly used for surgical tissue reconstruction due to its ease and lack of axial vascular limitation. However, ischemic necrosis is a common complication, especially in distal parts of skin flaps. Previous studies have shown that FGF21 can promote angiogenesis and protect against ischemic Cardiovascular Disease, but little is known about the effect of FGF21 on FLAP survival. In this study, using a rat model of random skin flaps, we found that the expression of FGF21 is significantly increased after establishment skin flaps, suggesting that FGF21 may exert a pivotal effect on FLAP survival. We conducted experiments to elucidate the role of FGF21 in this model. Our results showed that FGF21 directly increased the survival area of skin flaps, blood flow intensity, and mean blood vessel density through enhancing angiogenesis, inhibiting Apoptosis, and reducing oxidative stress. Our studies also revealed that FGF21 administration leads to an upregulation of Autophagy, and the beneficial effects of FGF21 were reversed by 3-methyladenine (3MA), which is a well-known inhibitor of Autophagy, suggesting that Autophagy plays a central role in FGF21's therapeutic benefit on skin FLAP survival. In our mechanistic investigation, we found that FGF21-induced Autophagy enhancement is mediated by the dephosphorylation and nuclear translocation of TFEB; this effect was due to activation of AMPK-FoxO3a-SPK2-CARM1 and AMPK-mTOR signaling pathways. Together, our data provides novel evidence that FGF21 is a potent modulator of Autophagy capable of significantly increasing random skin FLAP viability, and thus may serve as a promising therapy for clinical use.

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