2. Academic Validation
  3. Acetylcholine receptor-β inhibition by interleukin-6 in skeletal muscles contributes to modulating neuromuscular junction during aging

Acetylcholine receptor-β inhibition by interleukin-6 in skeletal muscles contributes to modulating neuromuscular junction during aging

  • Mol Med. 2024 Oct 10;30(1):171. doi: 10.1186/s10020-024-00943-3.
Yanling Zhao # 1,  Han Yan # 2,  Ke Liu # 2,  Jiangping Ma 2,  Wenlan Sun 1,  Hejin Lai 3,  Hongli Li 1,  Jianbang Gu 4,  He Huang 5 6
Affiliations

Affiliations

  • 1 Department of Geriatrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, P.R. China.
  • 2 Department of Neurology, Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, P.R. China.
  • 3 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 4 Department of Neurology, Shanghai Tenth People's Hospital Chongming Branch, Shanghai, 202150, P.R. China. jiandor36@126.com.
  • 5 Department of Neurology, Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, P.R. China. morton162@hotmail.com.
  • 6 Department of Neurology, Shanghai Tenth People's Hospital Chongming Branch, Shanghai, 202150, P.R. China. morton162@hotmail.com.
  • # Contributed equally.
PMID: 39390392 DOI: 10.1186/s10020-024-00943-3
Abstract

Background: Aging-related strength decline contributes to physiological deterioration and is a good predictor of poor prognosis. However, the mechanisms underlying neuromuscular junction disorders affecting contraction in aging are not well described. We hypothesized that the autocrine effect of interleukin (IL)-6 secreted by skeletal muscle inhibits acetylcholine receptor (AChR) expression, potentially causing aging-related strength decline. Therefore, we investigated IL-6 and AChR β-subunit (AChR-β) expression in the muscles and sera of aging C57BL/6J mice and verified the effect of IL-6 on AChR-β expression.

Methods: Animal experiments, in vitro studies, bioinformatics, gene manipulation, dual luciferase reporter gene assays, and chromatin immunoprecipitation experiments were used to explore the role of the transcription cofactor Peroxisome Proliferator-activated Receptor gamma coactivator 1-α (PGC1α) and its interacting transcription factors in the IL-6-mediated regulation of AChR-β expression.

Results: IL-6 expression gradually increased during aging, inhibiting AChR-β expression, which was reversed by tocilizumab. Both tocilizumab and the PGC1α agonist reversed the inhibiting effect of IL-6 expression on AChR-β. Compared to inhibition of signal transducer and activator of transcription 3, extracellular signal-regulated kinases 1/2 (ERK1/2) inhibition suppressed the effects of IL-6 on AChR-β and PGC1α. In aging mouse muscles and myotubes, myocyte enhancer factor 2 C (MEF2C) was recruited by PGC1α, which directly binds to the AChR-β promoter to regulate its expression.

Conclusions: This study verifies AChR-β regulation by the IL-6/IL-6R-ERK1/2-PGC1α/MEF2C pathway. Hence, evaluating muscle secretion, myokines, and AChRs at an earlier stage to determine pathological progression is important. Moreover, developing intervention strategies for monitoring, maintaining, and improving muscle structure and function is necessary.

Keywords

Acetylcholine receptor β; Aging; Interleukin-6; Myocyte enhancer factor 2 C; Neuromuscular junction; Peroxisome proliferator-activated receptor gamma coactivator 1α.

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