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.
- 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. [email protected].
- # Contributed equally.
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.