NRSA Fellowship for Gamboa: Skeletal Muscle Adaptation to Hypoxia

It has been suggested that mitochondrial dysfunction plays a major role in the pathogenesis of diabetes mellitus type 2. Reduced mitochondrial activity, primarily due to a preferential loss of subsarcolemmal mitochondria, has been proposed as one of the major responsible factors for the mitochondria dysfunction. Interestingly, high altitude mountaineers also present a similar pattern in mitochondrial content reduction. In addition, a recent gene expression analysis study in diabetic patients concfuded that hypoxia may be a possible trigger for the development of metabolic syndrome. However, there is no evidence that high altitude populations, chronically exposed to hypoxia, have a higher incidence of diabetes mellitus type 2, despite the reduction of mitochondrial oxidative capacity. The overall objective of the study is to define the mechanisms that underlie the reduction of mitochondrial oxidative capacity 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 mitochondrial 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-1 a will reverse the hypoxic-induced mitochondrial changes. Understanding the mitochondrial changes that occur during hypoxia will help to elucidate its potential role on the pathogenesis of diabetes mellitus type 2.