Skeletal muscle adaptation to hypoxia

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DESCRIPTION (provided by applicant): It has been shown that hypoxia could be detrimental for skeletal muscle mitochondria function. For instance, high altitude mountaineers present a reduction in subsarcolemmal rnitochondrial content; however, the exact mechanism that underlies this phenomenon has not been described. The same pattern of nitochondrial reduction has also been in muscle biopsies of patients with diabetes mellitus type 2 and a recent gene expression study in diabetic patients concluded that hypoxia may be a possible trigger for the development of metabolic syndrome. Mitochondrial abnormalities are also observed in patients with chronic obstructive pulmonary disease (COPD), a condition where hypoxia is prominent feature. Thus, the study of mitochondria! changes under hypoxic conditions is not only relevant to high altitude adaptation but to diseases states where hypoxia may play a pathogenic role. The overall objective of the study is to define the mechanisms that underlie the reduction of mitochondria) oxidative capacity in skeletal muscles under hypoxic conditions. We will use sedentary mice exposed to steady level of normobaric hypoxia to avoid confounding factors such as the hypoxia level and the physical activity. We will test the hypothesis that hypoxia will reduce the expression and protein levels of mitochondrial biogenic factors, particularly PGC-1a. In specific aim 1 we will evaluate the gene expression and protein level of the mitochondria! biogenic factor under hypoxic conditions, using the standard molecular biology techniques. Specific Aim 2 will evaluate the changes of mitochondrial oxidative capacity under hypoxic conditions. Mitochondrial respiration and enzymes activities will be measured for this purpose. In Specific Aim 3 we will test that the pharmacological activation of PGC-1a with resveratrol will reverse the hypoxic-induced mitochondrial changes in skeletal muscle. The comprehension of the mitochondria) changes that occur during hypoxia will help us to elucidate its potential role on the pathogenesis of diseases, such as diabetes mellitus type 2 and COPD, in order to develop new therapeutic strategies.