Role of Calpains in Uremia-Related Functional and Structural Muscle Changes: Protective Effect of Calpastatin Overexpression

Sarcopenia, the progressive loss of muscle mass and strength, is a common complication in patients with chronic kidney disease (CKD). This condition arises from a combination of factors including reduced physical activity, insufficient protein intake, hyperphosphatemia, chronic inflammation, and uremia itself; however, the underlying molecular mechanisms remain poorly understood. Proteolysis in skeletal muscle is primarily controlled by the ubiquitin-proteasome system, autophagy-lysosome system, and calpains (CAPNs) cysteine proteases, which degrade structural proteins and mediate cell signaling. This study aims to investigate the role of CAPNs in CKD-associated muscle deterioration. CKD was induced in mice through an adenine-rich diet for 2, 4 and 6 weeks. The involvement of CAPNs in CKD-related sarcopenia was assessed using mice that overexpressed the CAPNs endogenous inhibitor, calpastatin (CAST). Gastrocnemius muscle strength, structural integrity, and function were evaluated. Mice with CKD showed elevated CAPNs, particularly CAPN2, expression and activity in the gastrocnemius, in parallel with significant muscle deterioration, including strength loss, structural damage, and impaired muscle performance. Overexpression of CAST prevented muscle strength loss, improved muscle function and structure without affecting renal function, and reversed fibrosis, inflammation and adipogenesis expression markers. Targeting CAPN2 could be a promising therapeutic strategy to mitigate muscle damage and improve physical performance in CKD patients.