MON-592 Role Of Muscle-specific Fsp27 In Energy Production And Whole-body Glucose Homeostasis

Abstract Disclosure: R. Basri: None. B. Balakrishnan: None. M. Slayton: None. C. Becker: None. H. Hussein: None. I. Puri: None. A. Gupta: None. V. Sharma: None. C. Baumann: None. L. Consitt: None. V. Puri: None. Skeletal muscle (SkM) function is a critical determinant of numerous performance characteristics and whole-body energy metabolism, which influences systemic glucose homeostasis and overall metabolic health. Our study identifies a novel role of Fat-Specific Protein 27 (FSP27), previously characterized in adipose tissue and liver, as a key modulator of energy metabolism in skeletal muscle. We recently showed that FSP27 is highly expressed in SkM, and global Fsp27 knockout (Fsp27-/-) mice display markedly impaired energy balance and muscle function. To assess the muscle-specific role of FSP27 in SkM metabolism, we generated a muscle-specific Fsp27 knockout mouse model (M-Fsp27-/-). These mice exhibited significantly reduced ATP levels, citrate levels, and reduced energy expenditure compared to their floxed littermate controls, which highlights the critical role of SkM FSP27 in maintaining muscle bioenergetics. Our in vitro experiments confirmed the role of FSP27 in ATP production. Furthermore, M-Fsp27-/- mice displayed reduced running endurance and muscle strength, reinforcing the physiological impact of impaired energy metabolism. These results clearly showed that SkM-specific absence of FSP27 impairs both the energetic capacity and mechanical function of skeletal muscles. Notable, these impairments were observed in both sexes, indicating no sexual dimorphism. Mechanistically, we found that FSP27 interacts with lactate dehydrogenase A (LDHA), and its expression inversely regulates the rate of lactate production in SkM. Our loss and gain-of-function experiments in vitro confirmed the role of FSP27 on LDHA activity to produce lactate in SkM, indicating a regulatory role of FSP27 in glycolytic flux and substrate preference. Supporting these findings, our human data in young adults revealed a positive correlation between SkM FSP27 expression and performance metrics such as aerobic capacity, muscle strength, and responsiveness to exercise training, which are closely linked to efficient metabolic function and glucose homeostasis. As a systemic outcome, M-Fsp27-/- mice exhibited impaired glucose and insulin tolerance, highlighting the downstream impact of muscle energy deficiency on whole-body glucose homeostasis. Collectively, our findings establish FSP27 as a novel regulator of skeletal muscle energy metabolism, exerting effects on substrate utilization and whole-body glucose homeostasis. Presentation: Monday, July 14, 2025