SESN2 prevents the slow-to-fast myofiber shift in denervated atrophy via AMPK/PGC - 1α pathway

被引:13
作者
Yang, Xiaofan [1 ]
Xue, Pingping [2 ]
Liu, Zhenyu [1 ]
Li, Wenqing [3 ]
Li, Chuyan [3 ]
Chen, Zhenbing [1 ]
机构
[1] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Hand Surg, Wuhan 430022, Peoples R China
[2] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Pharm, Wuhan 430030, Peoples R China
[3] Huazhong Univ Sci & Technol, Union Shenzhen Hosp, Dept Hand & Foot Surg, Shenzhen 518052, Peoples R China
基金
中国国家自然科学基金;
关键词
Denervation; Skeletal muscle atrophy; Myofiber type transition; SESN2; AMPK/PGC-1; alpha; MUSCLE-FIBER-TYPE; SKELETAL-MUSCLE; SESTRIN; PGC-1-ALPHA; EXERCISE; SPECIFICITY; RESISTANCE; MICE;
D O I
10.1186/s11658-022-00367-z
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: Sestrin2 (SESN2), a stress-inducible protein, has been reported to protect against denervated muscle atrophy through unfolded protein response and mitophagy, while its role in myofiber type transition remains unknown. Methods: A mouse sciatic nerve transection model was created to evaluate denervated muscle atrophy. Myofiber type transition was confirmed by western blot, fluorescence staining, ATP quantification, and metabolic enzyme activity analysis. Adenoassociated virus (AAV) was adopted to achieve SESN2 knockdown and overexpression in gastrocnemius. AMPK/PGC-1 alpha signal was detected by western blot and activated with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). C2C12 myotubes with rotenone treatment were adopted for in vitro experiments. Results: SESN2 was found to be upregulated in denervated skeletal muscles and rotenone-treated C2C12 cells. Knockdown of SESN2 aggravated muscle atrophy and accelerated myofiber type transition from slow-twitch to fast-twitch. Moreover, AMPK/PGC-1 alpha signaling was proven to be activated by SESN2 after denervation, which further induced the expression of hypoxia-inducible factor HIF2 alpha. Exogenous activation of AMPIVPGC-1 alpha signaling could counteract the addition of slow-to-fast myofiber shift caused by SESN2 knockdown and lead to the retainment of muscle mass after denervation. Conclusion: Collectively, the present study indicates that SESN2 prevents myofiber type transition from slow-twitch to fast-twitch and preserves muscle mass in denervated atrophy via AMPK/PGC-1 alpha signaling. These findings contribute to a better understanding of the pathogenesis of muscle atrophy and provide novel insights into the role of SESN2 in myofiber type transition.
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页数:18
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