Mechamism of Activation of Oxidative Metabolism in vivo During Exercise

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DESCRIPTION (provided by applicant): Conditions (such as aging) or diseases (such as diabetes and cystic fibrosis) can cause chronic changes in oxygen transport and cellular metabolism. A computational model of skeletal muscle energy metabolism during exercise and hypoxia can be use to investigate the regulation of oxygen utilization and cellular metabolism in skeletal muscle. This model will include detailed cellular pathways of glycolysis, fatty acid oxidation, oxidative phosphorylation, and the citric acid cycle. Model simulations can then be used to analyze and predict metabolic responses to increased work rate in trained and untrained animals, healthy young and old subjects, and patients with diabetes and cystic fibrosis. Non-invasive measurements of pulmonary oxygen uptake can be used as diagnostic and/or treatment tools for conditions such as aging and diseases such as diabetes and cystic fibrosis. However, the dynamics of pulmonary oxygen uptake at the mouth are two orders of magnitude slower than intracellular metabolic dynamics. Therefore, a multi-level mathematical model is required to integrate cellular respiration with whole-body responses. Animal experiments will be used to explore the role of non-oxidative pathways. On the cellular level, the specific aim at this point is to determine the role of reducing equivalents in feedforward mechanisms regulating oxygen consumption. Experiments in dogs (normal and with altered dehydrogenase activity) will be conducted at rest and during exercise to quantify the potential effects of reducing equivalent availability on citric acid cycle flux and oxidative phosphorylation in skeletal muscle mitochondria.