8615 Unveiling The Muscle-Specific Role Of Fat-Specific Protein 27 In Regulating Muscle Performance 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, strength, and intrinsic muscle quality are closely linked to the pathogenesis and pathophysiology of metabolic disease. However, the regulatory molecular mechanisms in SkM performance remain elusive. Our study identifies Fat-Specific Protein (FSP27) as a novel player in muscle function. FSP27, previously found to be expressed in adipose and liver, is highly expressed in skeletal muscles (SkM). We recently found that the global FSP27 knockout (Fsp27-/-) mice have severely reduced muscle performance. Also, our human data identified a positive correlation of SkM FSP27 expression with indices of muscle performance such as aerobic capacity, muscle strength, and responsivity to exercise training. However, these studies could not explain the role of muscle-specific FSP27 Therefore, to study the physiological and mechanistic role of SkM-specific FSP27, we generated a loss-of-function Fsp27 knockout mouse model through muscle-specific ablation of FSP27 (M-Fsp27-/-). Treadmill running and hanging-grid tests were performed to study exercise endurance and muscle strength, respectively. M-Fsp27-/- showed significantly reduced running endurance and reduced muscle strength. In addition, glucose and insulin tolerance were significantly reduced in M-Fsp27-/- mice, suggesting the effect of muscle-specific FSP27 in whole-body glucose homeostasis. No sexual dimorphism was observed in muscle-specific functions of FSP27 and its effect on whole-body glucose homeostasis, with females showing similar results to males. Moreover, M-Fsp27-/- mice showed reduced energy expenditure compared to their littermate floxed controls. Interestingly, we found that FSP27 interacts with lactate dehydrogenase A (LDHA), and the rate of lactate production was found to be negatively associated with FSP27 expression in the SkM, indicating the molecular role of FSP27 in substrate utilization. Overall, our results identify a novel role of FSP27 in regulating muscle performance and metabolism via its effect on substrate utilization to produce energy. Presentation: 6/1/2024