Diurnal variation in skeletal muscle mitochondrial function dictates time of day-dependent differences in exercise capacity

ABSTRACT Exercise impinges on almost all physiological processes at an organismal level and is a potent intervention to treat various diseases. Exercise performance is well established to display diurnal rhythm, peaking during the late active phase. However, the underlying molecular/metabolic factors and mitochondrial energetics that possibly dictate time-of-day exercise capacity remain unknown. Here, we have unraveled the importance of diurnal variation in mitochondrial functions as a determinant of skeletal muscle exercise performance. Our results show that exercise-induced muscle metabolome and energetics are distinct at ZT3 and ZT15. Importantly, we have elucidated key diurnal differences in mitochondrial functions that are well correlated with disparate time-of-day dependent exercise capacity. Providing causal evidence, we illustrate that loss of Sirtuin4 (SIRT4), a well-known mitochondrial regulator, abrogates diurnal variation in mitochondrial functions and consequently abolishes time-of-day dependent exercise performance. Therefore, our findings unequivocally demonstrate the pivotal role of baseline skeletal-muscle mitochondrial functions in dictating diurnal exercise capacity.