Muscle Rev-erb controls time-dependent adaptations to chronic exercise in mice

Abstract

Abstract The best time of the day for chronic exercise training and the mechanism underlying the timing effects is unclear. Here, we show that low-intensity, low-volume treadmill training in mice before sleep yields greater benefits than after waking for muscle contractile performance and systemic glucose tolerance. Baseline muscle performance also exhibits diurnal variations, with higher strength but lower endurance before sleep than after waking. Muscle-specific knockout of circadian clock genes Rev-erbα/β (Rev-MKO) in male mice eradicates the diurnal variations in both training and baseline conditions without affecting muscle mass, mitochondrial content, food intake, or spontaneous activities. Multi-omics and metabolic measurements reveal that Rev-erb suppresses fatty acid oxidation and promotes carbohydrate metabolism before sleep. Thus, the muscle-autonomous clock, not feeding or locomotor behaviors, dictates diurnal variations of muscle functions and time-dependent adaptations to training, which has broad implications in metabolic disorders and sports medicine as Rev-erb agonists are exercise mimetics or enhancers.