Activation of the hypoxia‐inducible factor pathway induced by PHD2 deficiency enhances the effect of running training in mice

Abstract

BackgroundRecently, altitude training has widely been accepted by elite athletes as an efficient way to improve the sea‐level performance. The adaptation to the deprivation of O2, which is called hypoxic response and mediated by hypoxia‐inducible factors (HIFs), seems to contribute to the benefit of altitude training. However, the veracity of this benefit is still controversial, and the effect of biological processes mediated by the HIF pathway on the improvement in exercise performance after exercise training, if any, needs to be demonstrated. The main regulator of HIFs activity is prolyl hydroxylase domain protein 2 (PHD2). Previous reports showed that Phd2 deficiency induced HIFs activation and subsequent hematopoietic and angiogenic adaptations (Minamishima et al., 2008, Takeda et al., 2007). Overall, we believe that the Phd2‐deficient mouse model enables us to elucidate the influence of the activated HIF pathway on the exercise training effect. We therefore hypothesised that the stabilization of HIFs and the subsequent hypoxic response induced by Phd2 deficiency contribute to the improvement in exercise training. To examine this hypothesis, we investigated the maximal exercise capacity of Phd2‐deficient mice before and after a 4‐week regimen of exercise training.MethodsBecause Phd2 knockout is embryonic lethal, estrogen receptor (ER) agonist‐induced Phd2 cKO mouse using Cre‐loxP system was used. Two weeks after tamoxifen, an estrogen‐agonist, maximal running test using a rodent treadmill was performed. Control mice (n = 16) and Phd2 cKO mice (n = 15) were then divided into two groups: trained and non‐trained. The mice in the training group underwent 4‐week treadmill training on a rodent treadmill. After 4‐week period, all mice of both groups were tested again for their maximal running capacity and were sacrificed for blood and tissue examination.ResultsBecause of Phd2 deficiency, HIF‐α proteins accumulated. In line with increases in plasma erythropoietin levels (P < 0.01), the Phd2 cKO mice exhibited marked increases in haematocrit values (P < 0.01) and haemoglobin concentrations (P < 0.01). Increased expression of plasma vascular endothelial growth factor (P < 0.05) induced angiogenesis in the skeletal muscle of the Phd2 cKO mice (P < 0.05). Importantly, trained Phd2 cKO mice showed a significantly higher gain in running time by a factor of approximately 1.53 compared with the trained control mice (P < 0.05, Figure). On the other hand, we did not find any difference between the non‐trained control and non‐trained Phd2 cKO mice (P = 0.21). Collectively, these data suggest that the combination of training and the activation of the HIF pathway is important for maximizing the effect of running training.ConclusionsWe concluded that the activation of the HIF pathway induced by PHD2 deficiency enhanced the effect of running training.Support or Funding InformationThis work was supported by a JSPS Grant‐in‐Aid for JSPS fellows (26‐3209).