| Author |
Zhao, YL; Yan, H; Liu, K; Ma, JP; Sun, WL; Lai, HJ; Li, HL; Gu, JB; Huang, H |
| Abstract |
BackgroundAging-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 beta-subunit (AChR-beta) expression in the muscles and sera of aging C57BL/6J mice and verified the effect of IL-6 on AChR-beta expression.MethodsAnimal 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-alpha (PGC1 alpha) and its interacting transcription factors in the IL-6-mediated regulation of AChR-beta expression.ResultsIL-6 expression gradually increased during aging, inhibiting AChR-beta expression, which was reversed by tocilizumab. Both tocilizumab and the PGC1 alpha agonist reversed the inhibiting effect of IL-6 expression on AChR-beta. 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-beta and PGC1 alpha. In aging mouse muscles and myotubes, myocyte enhancer factor 2 C (MEF2C) was recruited by PGC1 alpha, which directly binds to the AChR-beta promoter to regulate its expression.ConclusionsThis study verifies AChR-beta regulation by the IL-6/IL-6R-ERK1/2-PGC1 alpha/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. |
