CTRP1 regulates skeletal muscle differentiation through quality control of mitochondrial dynamics and function

Abstract

Mitochondrial dysfunction is a hallmark of myopathies and impaired skeletal muscle differentiation. Here, we demonstrate that C1q/TNF-related protein 1 (CTRP1) is essential for maintaining mitochondrial dynamics and supporting myogenic differentiation. Loss of CTRP1 in myoblasts and in skeletal muscle-specific-knockout (CTRP1 KO Delta ACTA) mice led to impaired myotube formation, reduced muscle fiber cross-sectional area, and decreased muscle strength. CTRP1 deficiency also shifted the muscle fiber composition from oxidative type IIA to glycolytic type IIB fibers, indicating a compromised mitochondrial capacity. At the cellular level, CTRP1 loss resulted in elongated and disorganized mitochondria with diminished cristae density, membrane potential, and oxidative respiration. These mitochondrial abnormalities are associated with defective recruitment of dynamin-related protein 1 (DRP1), a central mediator of mitochondrial fission. Restoring CTRP1 expression or performing mitochondrial transplantation in CTRP1-KO myoblasts rescued mitochondrial function and re-established differentiation capacity. Furthermore, CTRP1 expression progressively decreased in accordance with disease severity in skeletal muscle biopsies from patients with polymyositis, dermatomyositis, and Duchenne muscular dystrophy, supporting its potential relevance to human myopathies. Together, these findings identify CTRP1 as a novel regulator of mitochondrial quality and myogenic differentiation, highlighting its potential as a therapeutic target for mitochondrial myopathies.