title: Activation of the hypoxia-inducible factor pathway induced by prolyl hydroxylase domain 2 deficiency enhances the effect of running training in mice.
abstract: Hypoxic response mediated by hypoxia-inducible factor (HIF) seems to contribute to the benefit of endurance training. To verify the direct contribution of HIF activation to running training without exposure to atmospheric hypoxia, we used prolyl hydroxylase domain 2 (PHD2) conditional knockout mice (cKO), which exhibit HIF activation independent of oxygen concentration, and we examined their maximal exercise capacity before and after 4 weeks of treadmill exercise training.
  
  
  
  Phd2f/fmice (n = 26) and Phd2 cKO mice (n = 24) were randomly divided into two groups, trained and untrained, and were subjected to maximal running test before and after a 4-week treadmill-training regimen.
  
  
  
  Prolyl hydroxylase domain 2 deficiency resulted in HIF-α protein accumulation. Phd2 cKO mice exhibited marked increases in haematocrit values and haemoglobin concentrations, as well as an increase in the capillary number in the skeletal muscle. The 4-week training elicited an increase in the capillary-to-fibre (C/F) ratio and succinyl dehydrogenase activity of the skeletal muscle. Importantly, trained Phd2 cKO mice showed a significantly greater improvement in running time than trained control mice (P < 0.05). Collectively, these data suggest that the combination of training and the activation of the HIF pathway are important for maximizing the effect of running training.
  
  
  
  We conclude that the activation of the HIF pathway induced by PHD2 deficiency enhances the effect of running training.
authors.affiliation: Department of Medicine and Science in Sports and Exercise, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nunomiya
authors.affiliation: Division of Biomedical Engineering for Health & Welfare, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Shin
authors.affiliation: Division of Biomedical Engineering for Health & Welfare, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kitajima
authors.affiliation: Division of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Dan
authors.affiliation: Division of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Department of Medicine and Science in Sports and Exercise, Tohoku University Graduate School of Medicine, Sendai, Japan.|Division of Biomedical Engineering for Health & Welfare, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan.|Center for Sports Medicine and Science, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: R
authors.identifier: 0000-0003-3038-7202
authors.initials: R
authors.lastname: Nagatomi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010805:Physical Conditioning, Animal / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D012420:Running; D015398:Signal Transduction
chemical_list: D051793:Hypoxia-Inducible Factor 1; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: altitude training; hypoxic response; training effect; treadmill