Loss Of Arnt Limits Skeletal Muscle Performance In Response To Aerobic Exercise
Yuteng Zhang1,2, Yori Endo1, Indranil Sinha1.
1Brigham and Women's Hospital, Boston, MA, USA, 2Nanfang Hospital, Southern Medical University, Guangzhou, China.
PURPOSE: The hypoxia signaling pathway is essential for angiogenesis and metabolic regulation during muscular adaptation to exercise. We have previously demonstrated that hypoxia signaling and levels of aryl hydrocarbon receptor nuclear translocator (ARNT), in particular, decline substantially with aging. To explore the role of ARNT in exercise performance, we generated a transgenic mouse model with inducible, skeletal muscle-specific knockout of ARNT upon tamoxifen activation (ARNT mKO).
METHODS: Both ARNT mKO and ARNT WT mice were subjected to sedentary activity (no regimented running) or treadmill running exercise regime at an increasing speed from 8-12 m/min for 40 minutes, three times weekly, over the course of 8 weeks.
RESULTS: ARNT mKO mice exhibit a 2-fold reduction in ARNT protein levels and 95% reduction in ARNT RNA expression. No difference was observed in capillary density or femoral blood flow between ARNT WT (littermate control) and ARNT mKO mice 10 days following tamoxifen activation. After training, the mice which had undergone the exercise regime exhibited 52% greater increase over the sedentary group in exercise endurance as measured by the maximum distance of running (490.92▒154.28 vs 237.76▒135.19 meters, p<0.01). In contrast, ARNT mKO mice did not benefit from the exercise training, demonstrating similar endurance to that of the sedentary ARNT mKO mice (231.85▒198.61 vs 167.27▒136.56 meters, p=0.41). In comparison to the exercised littermate, similarly trained ARNT mKO mice exhibited 53% lower running capacity. Similarly, the maximum running speed was severely restricted in the trained ARNT mKO mice versus the trained ANRT WT mice (16▒1.63 vs 26.67▒2.45 m/min, p<0.001). Interestingly, the exercise training increased femoral artery blood flow by 36% in ARNT WT mice (1030.74▒196.28 vs 664.33▒147.86 mm│/min, p<0.001), while no increase was observed in exercised ARNT mKO mice versus sedentary ARNT mKO mice (898.96▒52.33 vs 802.86▒48.43 mm│/min, p=0.20).
CONCLUSION: Collectively, these data suggest that ARNT is critical for the physiological response to exercise. Furthermore, age-related loss of ARNT may limit exercise-induced improvement in aerobic exercise capacity in aging.
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