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。运动和缺氧时骨骼肌能量代谢的计算模型可用于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，模型模拟可以用于分析和预测训练和未训练的动物、健康的年轻人和老年人以及糖尿病和囊性纤维化患者对增加工作率的代谢反应。肺摄氧量的无创测量可作为诊断和/或治疗工具，用于诸如衰老和疾病，如糖尿病和囊性纤维化。然而，口腔肺部摄氧量的动态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整合细胞呼吸和全身反应。动物实验将用于探索非氧化途径的作用。在细胞水平上，这一点的具体目的是确定减少等量物在调节氧气消耗的前馈机制中的作用。将在狗（正常和脱氢酶活性改变的狗）休息和运动时进行实验，以量化减少等效可用性对骨骼肌线粒体中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.