Mechamism of Activation of Oxidative Metabolism in vivo During Exercise

描述(由申请人提供)：条件(如衰老)或疾病(如糖尿病和囊性纤维化)可导致氧气运输和细胞代谢的慢性变化。运动和低氧条件下骨骼肌能量代谢的计算模型可以用来研究骨骼肌氧利用和细胞代谢的调节。该模型将包括糖酵解、脂肪酸氧化、氧化磷酸化和柠檬酸循环的详细细胞途径。然后，可以使用模型模拟来分析和预测训练有素和未训练有素的动物、健康的年轻和老年受试者以及糖尿病和囊性纤维化患者对工作率增加的代谢反应。肺摄氧量的非侵入性测量可用作衰老等疾病以及糖尿病和囊性纤维化等疾病的诊断和/或治疗工具。然而，口腔肺摄氧量的动力学比细胞内代谢动力学慢两个数量级。因此，需要一个多层次的数学模型来将细胞呼吸与全身反应结合起来。动物实验将被用来探索非氧化途径的作用。在细胞水平上，这一点的具体目标是确定减少当量在调节氧气消耗的前馈机制中的作用。在狗身上(正常和脱氢酶活性改变的狗)将在休息和运动中进行实验，以量化减少等量可利用性对骨骼肌线粒体柠檬酸循环通量和氧化磷酸化的潜在影响。

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.