Exercise preconditioning prevents immobilization-induced skeletal muscle atrophy by activating Prmt1-p38/ATF2-Sesn1 signaling axis in C57BL/6J mice

Abstract

Purpose: This study aimed to explore the effects of a 10-week combined exercise regimen on immobilization-induced muscle atrophy and elucidate the possible function of Protein arginine methyltransferase 1 (Prmt1) in this process.

Methods: 8-week-old male C57BL/6J mice were carried out combined exercise for 10 weeks. One week before the end of the intervention, mice underwent cast immobilization. Additionally, to investigate the potential mechanism in exercise-induced protection of skeletal muscle, mice in the exercise preconditioning group were administered TC-E-5003(an inhibitor of Prmt1 enzymatic activity). Exercise performance, muscle mass, and the cross-sectional area (CSA) of muscle fibers were analyzed. Besides, Prmt1 and Sestrin1 (Sesn1) were either overexpressed or inhibited in C2C12 myotubes to elucidate the underlying mechanism.

Results: Exercise preconditioning not only significantly improved muscle mass and motor ability in immobilized mice but also inhibited excessive activation of degradation pathways and enhanced protein synthesis. Importantly, Prmt1 mediated the protective effects of exercise preconditioning on muscle atrophy. Mechanistically, Prmt1 regulated the p38 mitogen-activated protein kinase (p38)/activating transcription factor 2 (ATF2) pathway, which modulates Sesn1 expression. Sesn1 acts as a downstream of Prmt1 and ATF2, contributing to the myoblast differentiation and skeletal muscle regeneration through AMP-Activated protein kinase α2 (AMPKα2)/transcriptional co-activator PPAR-γ co-activator-1 α (PGC-1α) signaling pathway.

Conclusions: Taken together, our results highlighted the effectiveness of exercise preconditioning in preventing muscle atrophy via the Prmt1-Sesn1 pathway.

Keywords

Prmt1 / Skeletal muscle atrophy / Immobilization / Sesn1 / ATF2 / PGC-1α

CRediT authorship contribution statement

Xuege Yang: Writing - original draft, Validation, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Yuchen Zou: Investigation, Formal analysis, Data curation, Writing -review & editing, Supervision, Funding acquisition. Haoyu Wang: Investigation, Data curation. Yanmei Niu: Supervision, Project admin-istration, Funding acquisition, Formal analysis, Conceptualization. Li Fu: Writing - review & editing, Funding acquisition.

Ethical approval statement

The mice were housed in a temperature-controlled environment of 22 ℃-24 ℃, and 40%-70% humidity, with 12 h light/dark cycles and received food and water ad libitum. All animal experiments were per-formed in accordance with Tianjin Medical University Animals Care and Use Committee and carried out following the Chinese Academy of Sci-ences guidelines (approval number: SYXK-2019-0004).

Declaration of competing interest

The authors declare the following financial interests/personal re-lationships 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.

Acknowledge Statement

The authors would like to thank our lab members, Dr.Song Huang for his technical assistance. This study was funded by research grants from the National Natural Science Foundation of China (32171135 and 32371168).

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.smhs.2025.04.001.

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