Age-dependent loss of Crls1 causes myopathy and skeletal muscle regeneration failure

Abstract Skeletal muscle aging results in the gradual deterioration of myogenesis, leading to muscle mass loss. However, the precise role of cardiolipin in myogenesis remains unclear. This study investigated the crucial role of mitochondrial cardiolipin and cardiolipin synthase 1 (Crls1) in age-related muscle deterioration and myogenesis. Our findings demonstrate that both cardiolipin and Crls1 are downregulated in aged skeletal muscles. Moreover, the knockdown of Crls1 in myoblasts resulted in reduced mitochondrial mass, activity, and expression of OXPHOS complex IV, along with the destruction of the mitochondrial cristae structure. AAV9-shCrls1-mediated downregulation of Crls1 impaired regeneration in a mouse model of cardiotoxin (CTX)-induced muscle damage, whereas Crls1 overexpression using AAV9-mCrls1 improved regeneration in an aging animal model of CTX-induced damage. Overall, our results highlight that the age-dependent decrease in Crls1 expression contributes to muscle loss by diminishing mitochondrial quality in skeletal muscle myoblasts. These findings suggest that modulation of Crls1 expression holds promise as a therapeutic strategy for mitigating muscle deterioration associated with aging, offering potential avenues for developing interventions to improve overall muscle health and quality of life in the elderly.