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12 jun 2012

Genes, altitude and health.

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Aerobic performance is clearly affected by the relative hypoxia at altitude as was noticed during the Olympic Games at Mexico City in 1968. Studies by our group (1) confirmed that already at 900 meters above sea level the elite athletes decrease significantly their VO2max. During exposure to altitude the human body initiates several physiological adaptations.

Autor(es): Nicolás Terrados Cepeda
Entidades(es): Universidad de Oviedo
Congreso: International symposium of altitude training
Granada 2008
ISBN:9788461235193
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Genes, altitude and health.

Aerobic performance is clearly affected by the relative hypoxia at altitude as was noticed during the Olympic Games at Mexico City in 1968. Studies by our group (1) confirmed that already at 900 meters above sea level the elite athletes decrease significantly their VO2max. During exposure to altitude the human body initiates several physiological adaptations. The stimulus of hypoxia associated with the training stimulus seemed to induce improvements in the enzymes, myoglobin, capillaries and haemoglobin (2,3,4,5,6,7). It further was established that hypoxia/ischemia-related metabolic perturbation is likely to be involved as stimuli in this process in human skeletal muscle. There is a marked individual variability in the response to altitude (8). This variability to both natural and simulated altitude, is only partially explained by physiological factors related to O2 delivery to tissues.

While some investigators have reported substantial increases in red cell mass following exposure to moderate altitude, other studies have found no change in haemoglobin mass after exposure to similar altitude (8). It is plausible, thus, that genetic polymorphisms may explain, at least in part, such variable responses to moderate-altitude exposure (9). In or study at Teide mountain at Canarias Islands (9), we verify that short term natural exposure to moderate altitude is a powerful stimulus for erythorpoietic response in endurance athletes showing a great individual variability. This biological response was not modified by the ACE gene polymorphism. Recently studies of adaptive mechanisms to hypoxia led to the discovery of the transcription factor called hypoxia inducible factor (HIF). HIF is a ubiquitously expressed, heterodimeric transcription factor that regulates a cassette of genes that can provide compensation for hypoxia, metabolic compromise, and oxidative stress including erythropoietin, vascular endothelial growth factor, or glycolytic enzymes (10). Also being responsible of increases of the plasma membrane lactate transporter MCT4, like other glycolytic enzymes, that is upregulated by hypoxia through a HIF-1alpha-mediated mechanism. This adaptive response allows the increased lactic acid produced during hypoxia to be rapidly lost from the cell (11).

Diseases associated with oxygen deprivation and consequent metabolic compromise such as stroke or Alzheimer’s disease may result from inadequate engagement of adaptive signalling pathways that culminate in HIF activation. The discovery that HIF stability and activation are governed by a family of dioxygenases called HIF prolyl 4 hydroxylases (PHDs) identified a new target to augment the transcriptional activity of HIF and thus the adaptive machinery that governs neuroprotection. PHDs lose activity when cells are deprived of oxygen, iron or 2-oxoglutarate. Inhibition of PHD activity triggers the cellular homeostatic response to oxygen and glucose deprivation by stabilizing HIF and other proteins. Of medical importance is that HIF transcription factors could have a role as oncogenes. As a consequence of HIF stabilisation, the cell constitutively up-regulates the hypoxic programme resulting in the expression of genes responsible for global changes in cell proliferation, angiogenesis, metastasis, invasion, de-differentiation and energy metabolism. Of note, its role in tumour angiogenesis, squamous cell carcinoma, ovarian clear cell carcinoma, and kidney function and disease. It is also very important to take into account that the modulation of HIF regulating pathways is a potential therapeutic target that may have benefits in the treatment of cancer (12).

References

1. Terrados, N., Mizuno, M., and E. Andersen. Reduction in maximal oxygen uptake at low altitudes; role of training status and lung function. Clinical Physiology. (Oxf.). 5 (supp.3): 75-80, 1985.

2. Terrados N, Melichna J, Sylven C, Jansson E, Kaijser L. Effects of training at simulated altitude on performance and muscle metabolic capacity in competitive road cyclists. Eur J Appl Physiol Occup Physiol.;57(2):203-9. 1988

3. Terrados, N., Jansson, E., Sylven, C., and L. Kaijser. Is hypoxia a stimulus for synthesis of oxidative enzymes and myoglobin? J Appl Physiol. 68: 2369-2372, 1990.

4. Terrados, N., Jansson, E., Norman, B., and L. Kaijser. Increased inosine 5- monophosphate accumulation despite no sign of increased glycolytic rate during one-legged exercise at simulated high altitude. Scand J Med Sci Sports. 2: 7-9, 1992.

5. Jansson, E., Terrados, N., Norman, B., and L. Kaijser. Effects of training at simulated high altitude on exercise at sea level. Scand J Med Sci Sports. 2: 2-6, 1992.

6. Terrados, N. Altitude training and muscular metabolism. Int J Sports Med. 13, Suppl.1:206-209, 1992.

7. Saltin, B., Kim, C.K., Terrados, N., Larsen, H., Svedenhag, J., and C.F. Rolf. Morphology, enzyme activities and buffer capacity in leg muscles of Kenyan and Scandinavian runners. Scand J Med Sci Sports. 5: 222-230. 1995.

8. Ge RL, Witkowski S, Zhang Y, Alfrey C, Sivieri M, Karlsen T, Resaland GK, Harber M, Stray-Gundersen J, Levine BD.Determinants of erythropoietin release in response to shortterm hypobaric hypoxia. J Appl Physiol.; 92(6):2361-7. 2002

9. González AJ, Hernández D, De Vera A, Barrios Y, Salido E, Torres A, Terrados N.ACE gene polymorphism and erythropoietin in endurance athletes at moderate altitude. Med Sci Sports Exerc.;38(4):688-93. 2006

10. Aragonés J, Schneider M, Van Geyte K, Fraisl P, Dresselaers T, Mazzone M, Dirkx R, Zacchigna S, Lemieux H, Jeoung NH, Lambrechts D, Bishop T, Lafuste P, Diez-Juan A, Harten SK, Van Noten P, De Bock K, Willam C, Tjwa M, Grosfeld A, Navet R, Moons L, Vandendriessche T, Deroose C, Wijeyekoon B, Nuyts J, Jordan B, Silasi-Mansat R, Lupu F, Dewerchin M, Pugh C, Salmon P, Mortelmans L, Gallez B, Gorus F, Buyse J, Sluse F, Harris RA, Gnaiger E, Hespel P, Van Hecke P, Schuit F, Van Veldhoven P, Ratcliffe P, Baes M, Maxwell P, Carmeliet P. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet. Jan 6. 2008

11. Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem. 7;281(14):9030-7. 2006

12. Calzada MJ, del Peso L. Hypoxia-inducible factors and cancer. Clin Transl Oncol.;9(5):278-89. 2007

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