Adaptation to Intermittent Hypoxia/Hyperoxia Enhances Efficiency of Exercise Training

  • Tatyana G. Sazontova
  • Antonina V. Bolotova
  • Irina V. Bedareva
  • Nadezhda V. Kostina
  • Yuriy V. Arkhipenko


This chapter provides an overview of the current concepts on redox signaling pathways, particularly, under hypoxic conditions. The principle of intermittent adaptation effects of variable oxygen levels (short-term hypoxia and hyperoxia) was substantiated and confirmed experimentally in vivo for the first time. The goal of our experiments in rats was to estimate (1) efficiency of physical training conducted separately and in combination with adaptation to intermittent hypoxia/hyperoxia, (2) changes in the rates of free radical processes, and (3) concentration of heat shock proteins (HSP). We found that short-term physical training increased the duration of swimming in acute exhaustive exercise. Combination of physical training with adaptation to hypoxia–normoxia had no effect on this parameter, while adaptation to physical load combined with adaptation to hypoxia–hyperoxia increased the duration of the active swimming phase and, as a consequence, the efficiency of adaptation. Adaptation to physical load and its combination with adaptation to variable oxygen levels increased the resistance of membrane structures to free radical oxidation at the expense of excessive activation of antioxidant defense enzymes in the course of physical training, which was partly compensated for by adaptation to hypoxia/normoxia and was fully prevented by adaptation to hypoxia/hyperoxia. Combination of two forms of adaptation to physical load and to variable oxygen levels markedly compensated/reversed the elevated content of HSP in the course of physical training, which is especially well pronounced during adaptation to hypoxia/hyperoxia. The novel technique is biologically less expensive and more beneficial for the organism.


Reactive Oxygen Species Reactive Oxygen Species Generation Physical Training Intermittent Hypoxia Damage Factor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Acute exhaustive exercise


Activator protein 1




Hydrogen peroxide






Hypoxia-inducible factor


Hydroperoxyl radical


Heat shock protein


Intermittent hypoxia


Iron-regulatory protein


Peroxy radicals


Lipid hydroperoxides


Nuclear factor kappa B


Nitric oxide


Superoxide anion radical


Hydroxyl radical


Reactive oxygen species


Superoxide dismutase


  1. 1.
    Das DK. Redox regulation of cardiomyocyte survival and death. Antioxid Redox Signal. 2001;3:23–37.PubMedCrossRefGoogle Scholar
  2. 2.
    Ungemach FR. Plasma membrane damage of hepatocytes following lipid peroxidation: involvement of phospholipase A2. In: Free radicals liver injury. Washington, D.C.: Oxford; 1985. p. 127–34. Proc. Int. Meet., Turin.Google Scholar
  3. 3.
    Sazontova TG. Stress-induced moderation of heart Ca-transporting system SR function and its resistance to endogenous damaging factors. Bull Exp Biol Med. 1989;108:271–4 [In Russian].CrossRefGoogle Scholar
  4. 4.
    Zolotarjova N, Ho C, Mellgren RL, et al. Different sensitivities of native and oxidized forms of Na+/K+-ATPase to intracellular proteinases. Biochim Biophys Acta. 1994;1192:125–31.PubMedCrossRefGoogle Scholar
  5. 5.
    Hemler ME, Cook HW, Lands WE. Prostaglandin biosynthesis can be triggered by lipid peroxides. Arch Biochem Biophys. 1979;193:340–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Roberts AM, Messina EJ, Kaley G. Prostacyclin (PGI2) mediates hypoxic relaxation of bovine coronary artery strips. Prostaglandins. 1981;21:555–69.PubMedCrossRefGoogle Scholar
  7. 7.
    Semenza GL. Perspectives on oxygen sensing. Cell. 1999;98:281–4.PubMedCrossRefGoogle Scholar
  8. 8.
    Chandel NS, Schumacker PT. Cellular oxygen sensing by mitochondria: old questions, new insight. J Appl Physiol. 2000;88:1880–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Flohe L, Brigelius-Flohe R, Salion C, et al. Redox regulation of NF-kappa B activation. Free Radic Biol Med. 1997;22:1115–26.PubMedCrossRefGoogle Scholar
  10. 10.
    Maulik N, Yoshida T, Das DK. Regulation of cardiomyocyte apoptosis in ischemic reperfused mouse heart by glutathione peroxidase. Mol Cell Biochem. 1999;196:13–21.PubMedCrossRefGoogle Scholar
  11. 11.
    Graven KK, Zimmerman LH, Dickson EW, et al. Endothelial cell hypoxia associated proteins are cell and stress specific. J Cell Physiol. 1993;157:544–54.PubMedCrossRefGoogle Scholar
  12. 12.
    Peng J, Jones GL, Watson K. Stress proteins as biomarkers of oxidative stress: effects of antioxidant supplements. Free Radic Biol Med. 2000;28:1598–606.PubMedCrossRefGoogle Scholar
  13. 13.
    Ryter SW, Tyrrell RM. The heme synthesis and degradation pathway: role in oxidant sensitivity. Free Radic Biol Med. 2000;28:289–309.PubMedCrossRefGoogle Scholar
  14. 14.
    Zhukova AG, Sazontova TG. Heme oxygenase: function, regulation, biological role. Hypoxia Med J. 2004;3–4:30–43.Google Scholar
  15. 15.
    Hu ML, Frankel EN, Leibowitz BE, et al. Effect of dietary lipids and vitamin E on in vitro lipid peroxidation in rat liver and kidney homogenates. J Nutr. 1989;119:1574–82.PubMedGoogle Scholar
  16. 16.
    Sanz MJ, Ferrndiz ML, Cejudo M, et al. Influence of a series of natural flavonoids on free radical generating systems and oxidative stress. Xenobiotica. 1994;24:689–99.PubMedCrossRefGoogle Scholar
  17. 17.
    Singh B, Sharma SP, Goyal R. Evaluation of Geriforte, an herbal geriatric tonic, on antioxidant defense system in Wistar rats. Ann N Y Acad Sci. 1994;717:170–3.PubMedCrossRefGoogle Scholar
  18. 18.
    Cai YN, Appelkvist EL, Deplerre JW. Hepatic oxidative stress and related defenses during treatment of mice with acetylsalicylic acid and other peroxisome proliferators. J Biochem Toxicol. 1995;10:87–94.PubMedCrossRefGoogle Scholar
  19. 19.
    Arkhipenko YuV, Sazontova TG, Rice-Evans C. Hypertrophy and regression of rat heart: free radical related metabolic systems. Pathophysiology. 1997;4:241–8.CrossRefGoogle Scholar
  20. 20.
    Kolchinskaya AZ. Intermittent hypoxic training in sports of highest achievements. Sports Med. 2008;1:9–25 [In Russian].Google Scholar
  21. 21.
    Sazontova TG, Tkatchouk EN, Kolmykova SN, et al. Comparative analysis of peroxidation and antioxidant enzyme activities in rats adapted to different regimes of normobaric hypoxia. Hypoxia Med J. 1994;2:4–7.Google Scholar
  22. 22.
    Sazontova TG, Arkhipenko YuV. The role of free-radical processes in adaptation of the organism to variable oxygen levels. In: Lukyanova LD, Ushakov IB, editors. Problems of hypoxia: molecular, physiological and medical aspects. Moscow: Publ. Istoki; 2004. p. 112–38 [In Russian].Google Scholar
  23. 23.
    Sazontova TG, Arkhipenko YuV. Intermittent hypoxia in resistance of cardiac membrane structures: role of reactive oxygen species and redox signaling. In: Xi L, Serebrovskaya TV, editors. Intermittent hypoxia: from molecular mechanisms to clinical applications. New York: Nova Science Publishers, Inc.; 2009. p. 147–87.Google Scholar
  24. 24.
    Zenkov NK, Lankin VZ, Menschikova EB. Oxidative stress. Moscow: MAIK Science/Interperiodica; 2001 [in Russian].Google Scholar
  25. 25.
    Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev. 1991;43:109–40.PubMedGoogle Scholar
  26. 26.
    Thomas S, Lowe JE, Hadjivassiliou V, et al. Use of the comet assay to investigate the role of superoxide in glutathione-induced DNA damage. Biochem Biophys Res Commun. 1998;243:241–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Skulachev VP. Mitochondrial in the programmed death phenomena; a principle of biology: “It’s better to die than to be wrong”. IUBMB Life. 2000;49:365–77.PubMedCrossRefGoogle Scholar
  28. 28.
    Sohal RS, Svensson I, Brunk UT. Hydrogen peroxide production by liver mitochondria in different species. Mech Ageing Dev. 1990;53:209–15.PubMedCrossRefGoogle Scholar
  29. 29.
    Beyer RE. The analysis of the role of coenzyme Q in free radical generation and as an antioxidant. Biochem Cell Biol. 1992;70:390–403.PubMedCrossRefGoogle Scholar
  30. 30.
    Zorov DB. Mechanisms of cardioprotection in hypoxia/reoxygenation. In: Reception and intracellular signaling. Puschino: Nauka; 2003. p. 160–2 [in Russian].Google Scholar
  31. 31.
    Sohal RS. Ageing, cytochrome oxidase activity, and hydrogen peroxide release by mitochondria. Free Radic Biol Med. 1993;14:583–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Richter C. Role of mitochondrial DNA modifications in degenerative diseases and aging. Curr Top Bioenerg. 1994;17:1–19.Google Scholar
  33. 33.
    Nikonorov AA, Tverdokhlib VP, Krasikov SI. Correction of biotransformation of xenobiotics in extreme states. In: Biochemistry: from molecular mechanisms investigation to implementation in clinical practice. Orenburg: OGMA; 2003. p. 305–11 [in Russian].Google Scholar
  34. 34.
    Deev LI, Ahalaya MYa, Illarionova EA, et al. Relation of changes in the content and activity of rat liver microsomal cytochrome P-450 to the intensification of lipid peroxidation under stress. Biull Eksp Biol Med. 1983;95:51–3 [In Russian].PubMedCrossRefGoogle Scholar
  35. 35.
    Nikonorov AA. Application of adaptation to interval hypobaric hypoxia for increase of sportsmen’ organism resistance to competition load. Thesis for MD. Siberian State Medical University, Tomsk; 2002 [In Russian].Google Scholar
  36. 36.
    Bondy SC, Naderi S. Contribution of hepatic cytochrome P450 systems to the generation of reactive oxygen species. Biochem Pharmacol. 1994;48:155–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Podmore I, Griffiths H, Herbert K. Vitamin C exhibits pro-oxidant properties. Nature. 1998;392:559.PubMedCrossRefGoogle Scholar
  38. 38.
    Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82:47–95.PubMedGoogle Scholar
  39. 39.
    Saenko YuV, Shutov AM. Role of oxidative stress in pathology of cardiovascular system in nephrologic patients. II. Clinical aspects of oxidative stress. Nephrol Dial. 2004;6:138–44.Google Scholar
  40. 40.
    Dubinina EE. Role of reactive oxygen species as signal molecules in tissue metabolism under oxidative stress. Vopr Med Khim. 2001;47:561–81 [In Russian].PubMedGoogle Scholar
  41. 41.
    Sergienko VI, Panasenko OM. Reactive oxygen species in disease pathogenesis. Technol Living Syst. 2004;1:37–46 [In Russian].Google Scholar
  42. 42.
    Moldovan NI, Moldovan L. Oxygen free radicals and redox biology of organelles. Histochem Cell Biol. 2004;122:395–412.PubMedCrossRefGoogle Scholar
  43. 43.
    Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84.PubMedCrossRefGoogle Scholar
  44. 44.
    Sies H. Oxidative stress – from basic research to clinical application. Am J Med. 1991;91:S31–8.CrossRefGoogle Scholar
  45. 45.
    Fridovich I. Fundamental aspects of reactive oxygen species, or what’s the matter with oxygen? Ann N Y Acad Sci. 1999;893:13–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Zakharova MN, Zavalishin IA, Boldyrev AA. Role of SOD in pathogenesis of amyotrophic lateral sclerosis. Bull Exp Biol Med. 1999;127:460–2 [In Russian].CrossRefGoogle Scholar
  47. 47.
    Wanders RJA, Denis S. Identification of superoxide dismutase in rat liver peroxisomes. Biochem Biophys Acta. 1992;1115:259–62.PubMedCrossRefGoogle Scholar
  48. 48.
    Akashi M, Hachiya M, Paquette RL. Irradiation increases manganese superoxide dismutase mRNA levels in human fibroblasts – possible mechanisms for its accumulation. J Biol Chem. 1995;270:15864–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Radi R, Turrens JF, Chang LY. Detection of catalase in rat heart mitochondria. J Biol Chem. 1991;266:22028–34.PubMedGoogle Scholar
  50. 50.
    Eriksson AM, Lundgren B, Andersson K, et al. Is the cytosolic catalase induced by peroxisome proliferators in mouse liver on its way to the peroxisomes? FEBS Lett. 1992;308:211–4.PubMedCrossRefGoogle Scholar
  51. 51.
    Antunes F, Han D, Cadenas E. Relative contributions of heart mitochondria glutathione peroxidase and catalase to H2O2 detoxification in in vivo conditions. Free Radic Biol Med. 2002;33:1260–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Finaud J, Lac G, Filaire E. Oxidative stress: relationship with exercise and training. Sports Med. 2006;36:327–58.PubMedCrossRefGoogle Scholar
  53. 53.
    Khotochkina LV, Statsenko NI. Intermittent hypoxic training as a method of physical state improvement and increase of efficiency in highly qualified oarsmen. Hypoxia Med J. 1993;2:38–40 [In Russian].Google Scholar
  54. 54.
    Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95:351–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Kikugawa K, Kojima T, Yamaki S, et al. Interpretation of the thiobarbituric acid reactivity of rat liver and brain homogenates in the presence of ferric ion and ethylenediaminetetraacetic acid. Anal Biochem. 1992;202:249–55.PubMedCrossRefGoogle Scholar
  56. 56.
    Luck H. Catalase. In: Bergmeyer HU, editor. Methods of enzymatic analysis. New York: Verlag-Chemie, Academic; 1963. p. 885–8.Google Scholar
  57. 57.
    Beauchamp C, Fridovich I. Superoxide dismutase: improved assay and an assay applicable to acrylamide gels. Anal Biochem. 1971;44:276–87.PubMedCrossRefGoogle Scholar
  58. 58.
    Andreeva LI, Goranchuk VV, Shustov EB, et al. Human adaptation to hypothermia and changes in leucocytes of peripheral blood. Sechenov Ross Physiol J. 2001;87:1208–16 [In Russian].Google Scholar
  59. 59.
    Boykova AA, Andreeva LI, Margulis BA, et al. Constitutive isoform of heat shock protein 70 in human blood mononuclears as marker of adaptation during normobaric hypoxia training. Sechenov Ross Physiol J. 2006;92:835–42 [In Russian].Google Scholar

Copyright information

© Springer-Verlag London 2012

Authors and Affiliations

  • Tatyana G. Sazontova
    • 1
  • Antonina V. Bolotova
    • 1
  • Irina V. Bedareva
    • 1
  • Nadezhda V. Kostina
    • 1
  • Yuriy V. Arkhipenko
    • 1
  1. 1.Faculty of Fundamental MedicineM.V. Lomonosov Moscow State UniversityMoscowRussia

Personalised recommendations