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

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.

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.

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.

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.