Exhaustive exercise abolishes REV‐ERB‐α circadian rhythm and shifts the kynurenine pathway to a neurotoxic profile in mice

The circadian-regulated transcriptional repressor REV-ERB-α is a key mediator of skeletal muscle oxidative capacity, enhancing exercise performance when activated. Conversely its global genetic ablation leads to impaired performance. Simultaneously the kynurenine (KYN) pathway, involved in tryptophan degradation, produces neurotoxic metabolites under stress and inflammation, contributing to CNS dysfunction and fatigue. These mechanisms may underlie the fatigue and performance impairments caused by exhaustive exercise (EE). This study investigated the interplay between REV-ERB-α and the KYN pathway in acute and chronic EE models. Time course analyses revealed that EE downregulated REV-ERB-α in skeletal muscle, correlated with KYN pathway alterations. Notably KYN metabolism shifted towards a neurotoxic profile, characterized by reduced KYN aminotransferase 1 (KAT1) and increased KYN 3-monooxygenase (KMO) expression in skeletal muscle, with increased KYN levels in the hippocampus. In vitro experiments using C2C12 myoblasts showed that REV-ERB-α knockout upregulated KAT1 and KMO, whereas overexpression selectively reduced KMO. Pharmacological activation of REV-ERB-α with SR9009 upregulated KAT1 in skeletal muscle and reduced KMO in the hippocampus of mice. These findings reveal a dynamic relationship between REV-ERB-α and the KYN pathway, linking peripheral and central responses to EE. This study highlights REV-ERB-α and the KYN pathway as critical regulators of exercise-induced fatigue and suggests potential therapeutic targets to mitigate its effects, offering novel insights into the molecular basis of performance impairments associated with EE. KEY POINTS: Excessive exercise can impair performance and induce fatigue; however the underlying biological mechanisms remain incompletely understood. Although REV-ERB-α activation enhances skeletal muscle oxidative capacity and exercise performance, its deletion impairs both parameters. This study demonstrates that excessive exercise decreases REV-ERB-α levels in skeletal muscle and disrupts the kynurenine (KYN) pathway by downregulating KYN aminotransferase 1 (KAT1), an enzyme involved in a neuroprotective branch of the pathway. These alterations affect both skeletal muscle and the brain, suggesting a potential link between physical fatigue and brain function. REV-ERB-α suppresses KYN 3-monooxygenase (KMO), a key enzyme in the KYN pathway that promotes the formation of potentially neurotoxic metabolites, thereby revealing a novel mechanism and a potential therapeutic target.