FGF21 augments autophagy in random-pattern skin flaps via AMPK signaling pathways and improves tissue survival
JournalCell Death and Disease
PublisherNature Publishing Group
MetadataShow full item record
AbstractRandom-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. Copyright 2019, The Author(s).
SponsorsThis work was supported by grants from Natural Science Foundation of China (No. 81601705 to K.Z., No. 81873992 to H.X., No. 81801930 to J.D.); Zhejiang Provincial Medicine and Health Technology Project (No. 2017KY472 to K.Z.); Wenzhou Science and Technology Bureau Foundation (No. 2016Y0350 to J.D.).
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85075136858&doi=10.1038%2fs41419-019-2105-0&partnerID=40&md5=0517c06cdbf66faa1263ee2975b3b8a5; http://hdl.handle.net/10713/11461