Mechamism of Activation of Oxidative Metabolism in vivo During Exercise

运动过程中体内氧化代谢激活的机制

• 批准号: 8015319
• 负责人: Jessica Rose Spires
• 金额: $ 4.08万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015319
• 关键词: Affect; Aging; Animal Experiments; Animals; Canis familiaris; Cell Respiration; Chronic; Citric Acid Cycle; Complex; Computer Simulation; Consumption; Cystic Fibrosis; Data; Diabetes Mellitus; Diagnostic; Disease; Electronics; Energy Metabolism; Energy Transfer; Exercise; FADH2; Generations; Glycolysis Pathway; Heart failure; Homeostasis; Human; Hypoxia; In Vitro; Lung; Measurement; Metabolic; Metabolism; Mitochondria; Modeling; Moderate Exercise; Muscle; Muscle Mitochondria; NADH; Oral cavity; Oxidative Phosphorylation; Oxidoreductase; Oxygen; Oxygen Consumption; Pathway interactions; Patients; Production; Publishing; Reaction; Regulation; Relative (related person); Research Training; Respiration; Respiratory Chain; Rest; Role; Signal Transduction; Skeletal Muscle; Testing; Tissues; Training; Work; adenylate; enzyme activity; fatty acid oxidation; in vivo; mathematical model; models and simulation; oxidation; oxygen transport; research study; response; tool; training project; uptake

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.

描述（由申请人提供）：条件（如老化）或疾病（如糖尿病和囊性纤维化）可导致氧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，模型模拟可用于分析和预测经过训练和未经训练的动物、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增加的工作率的代谢反应。肺氧摄取的非侵入性测量可以用作诸如老化和诸如糖尿病和囊性纤维化的疾病的状况的诊断和/或治疗工具。然而，在口腔处的肺氧摄取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整合细胞呼吸与全身反应。动物实验将用于探索非氧化途径的作用。在细胞水平上，此时的具体目标是确定还原当量在调节氧消耗的前馈机制中的作用。将在犬（正常和脱氢酶活性改变）中进行静息和运动期间的实验，以量化降低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。