The Regulation of CCN1 Contributes to Skeletal Muscle Wasting in Chronic Kidney Disease

BACKGROUND: Sarcopenia is a prevalent complication of chronic kidney disease (CKD), yet reliable biomarkers remain limited. CCN1, a matricellular protein involved in cellular senescence, has been implicated in muscle wasting, but its role in CKD-associated muscle strength decline is incompletely understood. METHODS: Serum CCN1 levels were measured by ELISA in 40 stage 3-5 CKD patients and 27 age-matched controls and correlated with handgrip strength (HGS). A 5/6 nephrectomy (NX) mouse model was established to evaluate muscle strength and senescence markers. C2C12 myotubes were treated with recombinant CCN1 or Wnt3a, with or without integrin β1 inhibitor or DKK-1. Senescence-associated β-galactosidase staining, qPCR, Western blot, co immunoprecipitation, and immunofluorescence were performed to explore mechanisms. RESULTS: GEO database analysis and our clinical data showed significantly elevated serum CCN1 levels in CKD patients versus controls. A trend toward a negative association was observed between serum CCN1 levels and HGS. In NX mice, reduced grip strength was associated with increased skeletal muscle CCN1 expression, upregulation of p53/p21/p16, and elevated Fbx32/Trim63. Co immunoprecipitation revealed physical interaction between CCN1 and integrin α6/β1. Blockade of integrin β1 attenuated CCN1 induced myotube senescence. Wnt3a dose dependently upregulated CCN1 and senescence markers, while DKK-1 partially reversed these effects. Serum from CKD mice with muscle wasting directly induced senescence in C2C12 myotubes, an effect also mitigated by DKK-1. CONCLUSIONS: CCN1 promotes muscle senescence through integrin α6/β1 signaling, with Wnt3a as an upstream regulator. CCN1 may serve as a potential biomarker for CKD related muscle wasting, and targeting the Wnt3a CCN1 integrin axis could represent a novel therapeutic strategy.