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 cardiac-enriched FHL2-interacting protein (CEFIP), a <i>Z</i>-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 level, CEFIP-deficient mice exhibited dampened expression of striated muscle activator of Rho signaling (<i>STARS</i>), a key mechanosensitive factor, whereas four-and-a-half LIM domain (<i>FHL</i>)<i>1</i> and <i>FHL3</i> were upregulated, with <i>FHL1</i> expression further increasing in response to exercise. Despite the overall compromised physical performance, CEFIP-deficient mice unexpectedly showed enhanced insulin responsiveness and increased muscular AMPK phosphorylation. Moreover, CEFIP-deficient mice exhibited heightened susceptibility to an exercise load, as evidenced by PGC-1α 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.<b>NEW & NOTEWORTHY</b> The authors identified CEFIP as a regulator linking exercise performance and metabolism, potentially through Z-disc-mediated mechanosensitive processes. CEFIP-deficient mice exhibited enhanced exercise-induced insulin response but impaired physical fitness, highlighting its complex role in balancing insulin sensitivity, glucose homeostasis, and muscle function. These findings underscore the necessity of proper CEFIP regulation for physiological homeostasis, though its precise role in wild-type mice remains unclear and warrants further investigation.