156. PHD2 in Old Skeletal Muscle Fibers Limits Exercise Response in Aging

PURPOSE: This study examines whether the physiological adaptation and molecular response to exercise change with aging. METHODS: To assess differential effects of aerobic exercise with age, Young (Y, 10-12 weeks) and Old (O, 23-25 months) mice were subjected to 8 weeks of treadmill running at a similar relative workloads or no regimented exercise. To assess the importance of hypoxia signaling in exercise response with aging, we generated mice with inducible, skeletal muscle fiber-specific knock-in of PHD2 (muscle (m)PHD2), which exhibited 6-fold higher levels of PHD2 in muscle compared to littermate controls. PHD2 is a critical upstream inhibitor of hypoxia signaling mPHD2 and control mice were similarly exercised or underwent no regimented exercise. RESULTS: Y, trained mice experienced a significant increase in maximal distance running, decreased fatigue with repeated tetanic stimulation, and a fiber type transition to oxidative fibers in comparison to age-matched, untrained controls. O mice did not improve significantly in these measures following training , Single nuclei RNA sequencing analysis of gastrocnemius from Y and O mice, both with and without exercise training, demonstrated a loss of hypoxia signaling within old myofibers. Prolyl hydroxylase domain 2 (PHD2) was found to be 5-fold higher in skeletal muscle at baseline and following exercise in O in contrast to Y mice. Following regimented exercise, mPHD2 mice did not improve maximal distance running, fatiguability, or exhibit a fiber type transition to oxidative fibers, whereas littermate control mice did. Administration of IOX2, a PHD2 inhibitor, increased maximal running distance and fiber type adaptation in response to exercise training in O mice. Additionally, peroxisome proliferator-activated receptor (PPAR) δ, a downstream target required for muscle adaptation to aerobic exercise, significantly increased in Y mice after training, but remained unchanged in O mice. CONCLUSION: Our results suggest that inhibition of PHD2 may restore exercise adaptation in aging.