Disuse-induced skeletal muscle IDO1 activation contributes to kynurenine-dependent muscle-liver crosstalk and hepatic oxidative injury.

Physical inactivity and mechanical unloading induce skeletal muscle atrophy and are associated with systemic metabolic disorders, but the molecular basis linking muscle disuse to liver injury remains unclear. Human cohort analyses (CHARLS, NHANES), a mouse hindlimb immobilization model, and multi-level in vitro systems were used to define this mechanism. Muscle disuse activates skeletal muscle indoleamine 2,3-dioxygenase 1 (IDO1), accompanied by altered tryptophan metabolism and increased systemic kynurenine accumulation. Kynurenine functioned as a circulating pathogenic mediator that activates hepatic aryl hydrocarbon receptor (AhR) signaling, resulting in oxidative stress, hepatocyte injury, and fibrotic remodeling. Importantly, pharmacological inhibition of IDO1 in vivo and siRNA-mediated IDO1 knockdown in vitro reduced kynurenine-associated AhR signaling and attenuated hepatocyte injury-related phenotypes. These findings identify an IDO1-kynurenine-AhR axis associated with muscle atrophy-related liver pathology and suggest that skeletal muscle IDO1 activation contributes to inter-organ metabolic communication during physical inactivity. Targeting this pathway may provide a therapeutic strategy to mitigate systemic complications associated with disuse and sedentary conditions.