Cellular Feimin enhances exercise performance by suppressing muscle thermogenesis

Exercise can rapidly increase core body temperature, and research has indicated that elevated internal body temperature can independently contribute to fatigue during physical activity. However, the precise mechanisms responsible for regulating thermogenesis in muscles during exercise have remained unclear. Here, we demonstrate that cellular Feimin (cFeimin) enhances exercise performance by inhibiting muscle thermogenesis during physical activity. Mechanistically, we found that AMPK phosphorylates cFeimin and facilitates its translocation into the cell nucleus during exercise. Within the nucleus, cFeimin binds to the forkhead transcription factor FOXC2, leading to the suppressed expression of Sarcolipin (Sln), which is a key regulator of muscle thermogenesis. In addition, our results further reveal that short-term AMPK agonist treatments can enhance exercise performance through the activation of the AMPK-cFeimin signaling pathway. In summary, these results underscore the crucial role of cFeimin in enhancing exercise performance by modulating SLN-mediated thermogenesis. To further assess the impact of cFeimin on exercise performance and energy utilization, we employed a low-intensity exercise protocol where mice ran at a constant speed equivalent to 60% of their maximal running speed. This protocol was employed for subsequent experiments in our study. In comparison to control littermates, cFeimin MKO mice exhibited reduced running time and distance compared to their WT little mates. The gastrocnemius muscles of sedentary (Sed) and 90-min exercised (Exe) fl/fl (WT) and cFeimin MKO (MKO) male mice were harvested for total RNA extraction, and RNA-seq analysis was performed.