CEFIP-deficiency in mice enhances glucose tolerance despite compromised muscle function.

Mechanotransduction in skeletal muscles is crucial for promoting global physical performance by coordinating muscular strength and metabolic properties, yet the underlying mechanisms and key regulatory molecules remain poorly understood. We identified CEFIP, a Z-disc localized protein upregulated upon contractility acquisition, as a potential integrator maintaining the balance between muscular performance and glucose metabolism. CEFIP deficiency resulted in decreased physical fitness, including lower running capabilities and weaker grip strength, even with no apparent myofiber disorganization. At the molecular levels, CEFIP-deficient mice exhibited dampened expression of STARS, a key mechanosensitive factor, while FHL1 and FHL3 were upregulated, with FHL1 expression further increasing in response to exercise. Despite the overall compromised physical performance, CEFIP-deficient mice unexpectedly led to enhanced insulin responsiveness, and increased muscular AMPK phosphorylation. Moreover, CEFIP-deficient mice exhibited heightened susceptibility to an exercise load, as evidenced by PGC-1a upregulation and augmented GLUT4 regulation, and enhanced insulin sensitivity, as indicated by sarcolemmal GLUT4 translocation. Taken together, our findings suggest that CEFIP serves as a key regulatory link between exercise performance and metabolic properties, potentially through Z-disc-mediated mechanosensitive processes in exercising skeletal muscles.