Acute Endurance Exercise Increases Hepatic Mitochondrial Function Potentially Mediated Through The Orphan Nuclear Receptor Nur77

Endurance exercise positively impacts mitochondrial health, however the mechanisms underlying these benefits are not fully understood. Nur77, a fasting-induced orphan nuclear receptor, is known to increase mitochondrial function in skeletal muscle. However, it is unknown if Nur77 affects hepatic mitochondrial function and whether expression is stimulated by exercise. PURPOSE: The purpose of this study was to investigate Nur77 expression following acute and chronic endurance exercise training and if its expression modulates exercise-induced changes in hepatic mitochondrial function. We hypothesized that Nur77 would increase in response to a single, acute bout of exercise and mediate changes in hepatic mitochondrial function. METHODS: Male and female 6-month-old Fischer 344 rats completed chronic or acute exercise or served as sedentary controls. Chronic exercise consisted of treadmill running 5 days per week for 8 weeks using a progressive protocol designed to maintain an intensity of 70% of VO2max (increasing grade and speed). Acute exercise consisted of a single 30-minute bout of treadmill running. Hepatic mitochondria were isolated or livers were flash frozen for RNA and protein analyses 48 hours after the last training bout and immediately after the acute exercise bout. RESULTS: Acute exercise increased hepatic Nur77 mRNA expression 23-fold and 39-fold in male and female rats, respectively (p < 0.0001), with a 2-fold increase in females versus male rats (p < 0.001). Acute exercise improved mitochondrial respiration in females, increasing state 3-complex I by 1.5-fold (p < 0.01) and state 3-complex I + II by 1.4-fold (p < 0.05). Chronic training increased protein content of OXPHOS complex I by 1.3-fold (p < 0.01), complex II by 1.2-fold (p < 0.05), and complex IV by 1.5-fold (p < 0.01) in females compared with sedentary controls. Complex II protein content was also increased in males by 1.1-fold (p < 0.05) compared with sedentary controls. Interestingly, hepatic Nur77 mRNA expression and mitochondrial respiratory parameters were not different between sedentary and chronically trained rat (p > 0.05). CONCLUSION: Here we reveal that a single bout of endurance exercise increases hepatic mitochondrial function in conjunction with elevated Nur77 expression, suggesting a potential mechanistic link. National Institute of Health (U01AG070928)