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).
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