2. Academic Validation
  3. Cyr61 promotes D-gal-induced aging C2C12 cell fibrosis by modulating Wnt/β-catenin signaling pathways

Cyr61 promotes D-gal-induced aging C2C12 cell fibrosis by modulating Wnt/β-catenin signaling pathways

  • Mech Ageing Dev. 2025 Jun:225:112067. doi: 10.1016/j.mad.2025.112067.
Xinchen Huang 1,  Xiaoling Kui 2,  Jiyao Ma 2,  Jiaxin Chen 2,  Yilong Huang 3,  Bo He 4
Affiliations

Affiliations

  • 1 Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China; Department of Radiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
  • 3 Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China. Electronic address: kmhuangyilong@qq.com.
  • 4 Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China. Electronic address: kmmu_hb@163.com.
PMID: 40339921 DOI: 10.1016/j.mad.2025.112067
Abstract

Sarcopenia is characterized by age-related muscle mass/function loss and fibrosis. Satellite cell (SC) dysfunction during aging promotes fibrotic transdifferentiation and extracellular matrix (ECM) deposition. Cyr61, a pro-fibrotic matricellular protein, and Wnt/β-catenin signaling pathway are implicated in muscle regeneration-fibrosis balance, but their interaction in sarcopenia remains unclear. This study first compared the expression of Cyr61 and fibrosis markers (TGF-β1, Collagen type I and III) in skeletal muscle of young and old mice. In vitro, D-gal-induced C2C12 aging models were used to assess Cyr61 and Wnt signaling pathway by proliferation/Apoptosis assays, ECM analysis, and detecting the changes of myogenic/fibrotic markers (MyoD, α-SMA). Pathway modulation (FH535 inhibitor/LiCl activator) and combined with Cyr61 overexpression and knockout experiments defined mechanistic roles. Cyr61 was upregulated in skeletal muscle of aged mice, which was positively correlated with increased TGF-β1 and Collagen deposition. In D-gal-induced C2C12 cells showed suppressed cell proliferation, increased Apoptosis and enhanced ECM deposition, accompanied by elevated Cyr61. Cyr61 knockdown or Wnt signaling pathway inhibition (FH535) reversed fibrosis (α-SMA, Collagen) and restored myogenesis (MyoD).This study reveals for the first time that Cyr61 drives sarcopenic fibrosis via Wnt/β-catenin activation, promoting myocyte-to-fibrotic transition. Targeting the Cyr61-Wnt axis may ameliorate age-related muscle degeneration, warranting translational validation in preclinical models.

Keywords

Aging; Cyr61; Fibrosis; Sarcopenia; Wnt signaling pathway.

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