Skeletal muscle‐specific PHD2 deficiency improved running endurance in mice

Abstract

IntroductionHypoxic training is one of the methods supposed to improve the performance of endurance athletes. Under a normoxic condition, prolyl hydroxylase domain containing protein 2 (PHD2) leads hypoxia inducible factor (HIF) to proteasomal degradation. Under hypoxia, PHD2 becomes inactive and let HIF be stabilized. HIF, then, promotes the expression of downstream genes, resulting in enhanced glycolysis, suppressed electron transport system, promotion of red blood cell production and angiogenesis. In PHD2 systemic knock‐out mice, hypoxic responses are elicited even under normoxia due to stabilized HIF. Interestingly, an enhanced endurance training effect was confirmed in PHD2 systemic knock‐out mice (Nunomiya et al. 2017). In PHD2 systemic knock‐out mice, calcineurin dependent increase in the proportion of type I fibers in skeletal muscles has been confirmed. (Shin et al. 2016). Whether the shift in fiber type, and more importantly the training effect is dependent on the hypoxic response within the muscle fibers or on the systemic hypoxic response has not been elucidated. The purpose of this study was to examine the effect of hypoxic response in skeletal muscle on the endurance training effect.MethodIn order to delete PHD2 specifically in skeletal muscle, doxycycline was administered for 18 days to PHD2flox/flox/Acta1rtTA/tetO‐Cre mice. The running time on a rodent treadmill until exhaustion was measured 8–10 days after the final administration of doxycycline before training and after 4 weeks of treadmill training, Endurance testing protocol: treadmill speed was set at 10 m/min for the initial 30 min, then after the speed was increased by 2 m/min every 15 min with no inclination. Training protocol: training was performed 5days per week for 4 weeks. Mice ran for 30 min per day. The running speed was 18m/min with 5 degrees uphill inclination.ResultIn PHD2flox/flox/Acta1rtTA/tetO‐Cre+/− mice, a significant reduction in PHD2 expression in gastrocnemius, tibialis anterior muscle, and soleus was confirmed. Skeletal muscle specific PHD2 knocked out mice had significantly increased endurance time compared to control mice before training. But there was no significant difference in the training effect between skeletal muscle‐specific PHD2‐deficient mice and control mice. There was no significant difference in training effect between skeletal muscle‐specific PHD2‐deficient mice and control mice.ConclusionHypoxic response in the skeletal muscle resulted in a higher endurance capacity without training. There was no additive training effect in the mice the mice with hypoxic response. It was suggested that systemic hypoxic response may be responsible for the additive endurance training effect confirmed in the previous study.