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

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

  • Cell Mol Biol Lett. 2022 Aug 9;27(1):66. doi: 10.1186/s11658-022-00367-z.
Xiaofan Yang  # 1 Pingping Xue 2 Zhenyu Liu 1 Wenqing Li 3 Chuyan Li 3 Zhenbing Chen 4
Affiliations

Affiliations

  • 1 Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 2 Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 3 Department of Hand and Foot Surgery, Union Shenzhen Hospital, Huazhong University of Science and Technology, Shenzhen, 518052, China.
  • 4 Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. zbchen@hust.edu.cn.
  • # Contributed equally.
Abstract

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. Adeno-associated virus (AAV) was adopted to achieve SESN2 knockdown and overexpression in gastrocnemius. AMPK/PGC-1α 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-1α signaling was proven to be activated by SESN2 after denervation, which further induced the expression of hypoxia-inducible factor HIF2α. Exogenous activation of AMPK/PGC-1α 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-1α 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.

Keywords

AMPK/PGC-1α; Denervation; Myofiber type transition; SESN2; Skeletal muscle atrophy.

Figures
Products