Back to Search
Start Over
Acetylcholine receptor-β inhibition by interleukin-6 in skeletal muscles contributes to modulating neuromuscular junction during aging.
- Source :
-
Molecular medicine (Cambridge, Mass.) [Mol Med] 2024 Oct 10; Vol. 30 (1), pp. 171. Date of Electronic Publication: 2024 Oct 10. - Publication Year :
- 2024
-
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.<br />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.<br />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.<br />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.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Male
Mice
Gene Expression Regulation drug effects
MEF2 Transcription Factors metabolism
MEF2 Transcription Factors genetics
Mice, Inbred C57BL
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism
Receptors, Cholinergic metabolism
Receptors, Nicotinic metabolism
Receptors, Nicotinic genetics
Aging metabolism
Interleukin-6 metabolism
Muscle, Skeletal metabolism
Muscle, Skeletal drug effects
Neuromuscular Junction metabolism
Neuromuscular Junction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1528-3658
- Volume :
- 30
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular medicine (Cambridge, Mass.)
- Publication Type :
- Academic Journal
- Accession number :
- 39390392
- Full Text :
- https://doi.org/10.1186/s10020-024-00943-3