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

Jidong Liu, Fang Xiao, Abhinav Choubey, Udhaya Kumar S, Yanxiang Wang, Sungguan Hong, Tingting Yang, Husniye Gul Otlu, Ege Sanem Oturmaz, Emanuele Loro, Yuxiang Sun, Pradip Saha, Tejvir S. Khurana, Li Chen, Xinguo Hou () and Zheng Sun ()
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Jidong Liu: Qilu Hospital of Shandong University
Fang Xiao: Shandong University
Abhinav Choubey: Baylor College of Medicine
Udhaya Kumar S: Baylor College of Medicine
Yanxiang Wang: Jinan AXZE Medical Test Laboratory
Sungguan Hong: Baylor College of Medicine
Tingting Yang: Baylor College of Medicine
Husniye Gul Otlu: Baylor College of Medicine
Ege Sanem Oturmaz: Baylor College of Medicine
Emanuele Loro: University of Pennsylvania
Yuxiang Sun: Qilu Hospital of Shandong University
Pradip Saha: Baylor College of Medicine
Tejvir S. Khurana: University of Pennsylvania
Li Chen: Qilu Hospital of Shandong University
Xinguo Hou: Qilu Hospital of Shandong University
Zheng Sun: Baylor College of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-17

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.

Date: 2025
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DOI: 10.1038/s41467-025-60520-y

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