Effects of endurance exercise on skeletal muscle and liver metabolic health in male rats with different fitness under chronic circadian rhythm disruption.

Background: Circadian rhythm (CR) disruption is a major risk factor for metabolic dysfunction in skeletal muscle and liver. Although endurance training (ETR) is known to improve metabolic health, it remains unclear whether exercise timing and training duration influences metabolic adaptations under CR disruption. Methods: Twenty-four male Sprague-Dawley rats were randomly assigned to four groups: regular sleep cycle sedentary (RSC), irregular sleep cycle sedentary (ISC), irregular sleep cycle with late-stage ETR (ISE), and irregular sleep cycle with prolonged ETR (IEE). CR disruption was induced by alternating light-dark cycles every three days for 20 weeks. ETR was performed at moderate intensity. Skeletal muscle and liver samples were analyzed for circadian clock proteins, mitochondrial biogenesis, glucose and lipid metabolism, oxidative stress, and fibrosis-related markers. Results: CR disruption significantly impaired circadian clock regulation, mitochondrial biogenesis, and metabolic function in both skeletal muscle and liver. Specifically, reductions in BMAL-1 expression, AMPK activation, PGC-1α signaling, and oxidative phosphorylation were observed, along with disrupted glucose and lipid metabolism. These alterations were accompanied by increased oxidative stress, hepatic lipid accumulation, and fibrosis-related markers. ETR effectively attenuated these changes. Notably, training initiated prior to CR disruption (or a higher fitness maintained during CR disruption) group (IEE) resulted in greater improvements in mitochondrial and metabolic adaptations compared with shorter-duration training (ISE). In contrast, no significant differences were observed between ISE and IEE in oxidative stress and fibrosis-related outcomes. Conclusions: Endurance training mitigates CR disruption-induced metabolic dysfunction in skeletal muscle and liver. Prolonged training exposure enhances mitochondrial and metabolic adaptations, whereas protective effects on oxidative stress and fibrosis may occur even with shorter training duration. These findings highlight the importance of exercise timing and training duration in optimizing metabolic resilience under circadian disruption.