Loss of ARNT Limits Improvement in Physiological Performance Following Aerobic Exercise in Aging

Abstract Hypoxia signaling is essential for angiogenesis and metabolic regulation during exercise. Our previous study has demonstrated an age-related loss of ARNT resulting in limited muscle regeneration. To explore the role of hypoxia signaling in physiological performance in relation to aging, we generated a mouse model with skeletal muscle-specific knockout of ARNT (ARNT mKO). ARNT mKO and ARNT WT mice were subjected to a sedentary activity or treadmill running exercise regime at an increasing speed of 8-12 m/min for 40 minutes, three times weekly over the course of 8 weeks. ARNT levels was 3-fold lower in old mice compared to young. The exercised WT mice exhibited 52% greater increase over the sedentary group in exercise endurance as measured by the maximum running distance (490.92±154.28 vs 237.76±135.19m, p＜0.01). In contrast, ARNT mKO mice did not benefit from exercise (231.85±198.61 vs 167.27±136.56m, p=0.41). The maximum running speed was severely restricted in the trained ARNT mKO mice versus WT (16±1.63 m/min vs 26.67±2.45 m/min, p＜0.001). Cross-sectional area of myofibers increased significantly following exercise in WT mice (2270 vs 2960 □m2, p=0,015) indicating muscle hypertrophic response, while no change was observed in the ARNT mKO group (2101 vs 2378□m2, p=0,21). Further, exercise increased femoral artery blood flow by 41% in ARNT WT mice, but not in ARNT mKO mice (898.96±52.33 vs 802.86±48.43, p=0.20). These data suggest that ARNT is essential for physiological response to exercise