Endurance training increases tmTNF-α and IL-6 levels in several vital organs in rats: relationship with hypoxia markers

Background: Although endurance training is known to induce systemic adaptations involving inflammatory and hypoxia-related signaling, tissue-specific protein responses remain incompletely understood. Therefore, this study examined the effects of endurance training on inflammatory cytokines and hypoxia markers across multiple organs. Methods: Male Wistar rats performed treadmill running (30-60 min/day, 5 days/week) for 8 weeks. Protein expression of interleukin 6 (IL-6), transmembrane tumor necrosis factor-alpha (tmTNF-α), soluble TNF-α (sTNF-α), hypoxia-inducible factor 1 subunit alpha (HIF-1α), and lysine demethylase 6A (KDM6A) was assessed in the lungs, liver, skeletal muscle, heart, and brain. Results: Endurance training increased IL-6 protein levels in the lungs, liver, skeletal muscle, and heart, but decreased them in the brain. It also increased tmTNF-α protein levels in the lungs, liver, skeletal muscle, and heart, but decreased them in the brain; it did not affect sTNF-α protein levels in any organ. Hypoxia markers responded to endurance training in an organ-specific manner: HIF-1α and KDM6A protein levels increased in the lungs, liver, and heart, whereas KDM6A protein levels increased while HIF-1α protein levels were unchanged or decreased in the brain and skeletal muscles, respectively. Conclusion: Endurance training induces organ-specific regulation of inflammatory and hypoxia-related proteins. The differential responses of TNF-α isoforms suggest distinct roles of local inflammatory signaling in exercise-induced adaptations. Of particular interest is the observed anti-inflammatory effect of endurance training in the brain, indicating distinct regulatory mechanisms within the CNS.