Resistance exercise alleviates skeletal muscle atrophy through reduction of oxidative stress via Sestrin1 in C57BL/6J mice

Abstract

Resistance exercise has been confirmed to be important for maintaining muscle mass and function. However, despite considerable experimental studies, the underlying mechanisms still requires further investigation to be elucidated. Sestrin1 is a stress-inducible protein strongly associated with the occurrence and development of skeletal muscle dysfunction. Besides, oxidative stress is believed to be a major pathogenic mechanism in the development of skeletal muscle atrophy, whereas regular exercise training induces the endogenous antioxidative system and protects the body against adverse effects of oxidative stress. Nevertheless, whether Sestrin1 is involved in the amelioration of resistance exercise on muscle atrophy and the role of its antioxidant function in this process remains unknown. Here we show that six-week resistance exercise training significantly improved muscle function, muscle mass, and oxidative damage and maintained the level of Sestrin1 in dexamethasone-treated C57BL/6J mice. Mechanistically, Sestrin1 overexpression rescued protein degradation and oxidative stress in atrophied myotubes. Furthermore, an emerging regulator of cellular defense against toxic and oxidative insults, nuclear factor erythroid2-related factor 2 (Nrf2) controls the basal and induced expression of an array of antioxidant response element-dependent genes to regulate the pathophysiological outcomes of oxidant exposure. In this study, we found that Nrf2 is a target of Sestrin1, and Nrf2 nuclear translocation is facilitated by Sestrin1. ML385 (an Nrf2 inhibitor) treatment mitigated the regulatory effects of overexpression-Sestrin1. Therefore, Sestrin1 was involved in the process of resistance exercise against skeletal muscle atrophy, which may be closely related to its antioxidant capacity, revealing a potential therapeutic strategy for reducing the loss of skeletal muscle.

Keywords

Resistance exercise / Muscle atrophy / Sestrin1 / Oxidative stress / Nrf2

CRediT authorship contribution statement

Xuege Yang: Writing - original draft, Visualization, Validation, Software, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Jinglin Peng: Investigation, Data curation. Yating Huang: Visualization, Methodology, Investigation, Data curation, Conceptualization. Sujuan Liu: Visualization, Validation, Project administration, Formal analysis, Conceptualization. Yanmei Niu: Visualization, Validation, Resources, Project administration, Formal analysis, Conceptualization. Li Fu: Writing - review & editing, Supervision, Resources, Funding acquisition, Conceptualization.

Ethical approval statement

Animals were housed at 22 ​°C-24 ​°C under 12 ​h dark and 12 ​h light cycle. Food and water were provided ad libitum during the experimental period. Animal experiments were approved by the Tianjin Medical University Animals Care and Use Committee and carried out following the Chinese Academy of Sciences guidelines (approval number: SYXK-2019-0004).

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Li Fu is an ​Editorial Board Member ​for ​Sports Medicine ​and Health Science and was not involved in the editorial review or the decision to publish this article. Li Fu reports the funding for this study was provided by National Natural Science Foundation of China.

Acknowledgements

The authors would like to thank members of our lab, and specially Mrs. Yang Yang, Chenxin Jiang for the technical supports and Dr. Chunxia Yu for the helpful suggestions. This study was funded by research grant from National Natural Science Foundation of China (32171135).

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.smhs.2025.02.001.

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