Identifying a novel role of FSP27 in skeletal muscle function and whole-body glucose homeostasis

Skeletal muscle (SkM) function and strength are closely linked to the pathogenesis and pathophysiology of metabolic disease. However, the regulatory molecular mechanisms in SkM performance remain elusive. Our study identifies a novel role of Fat-Specific Protein (FSP27) in muscle function. FSP27. We found that FSP27, previously found to be expressed in adipose, liver, and endothelium, is highly expressed in skeletal muscles (SkM). Recent study in our lab showed that the global FSP27 knockout (Fsp27-/-) mice have severely reduced muscle performance. Our present study determines the physiological and mechanistic role of SkM-specific FSP27 in muscle function and muscle strength. We generated a loss-of-function Fsp27 knockout mouse model through muscle-specific ablation of Fsp27 (M-Fsp27-/-). Treadmill running and hanging-grid tests exhibited significantly reduced running endurance and reduced muscle strength in M-Fsp27-/- mice compared to the floxed-controls. Also, 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. Mechanistically, 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 improving muscle performance and endurance via its effect on substrate utilization to produce energy and regulate muscle performance and metabolism. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.