Skeletal Muscle Basis for Improved Exercise Endurance in AC5 KO

AC5 KO 中提高运动耐力的骨骼肌基础

• 批准号: 8497469
• 负责人: STEPHEN F VATNER
• 金额: $ 43.02万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8497469
• 关键词: Adenosine; Affect; Aging; Antioxidants; Biogenesis; Biological Availability; Blood flow; Cardiac; Cardiac Output; Cardiomyopathies; Cardiovascular Diseases; Catecholamines; Cell model; Cells; Chronic; Data; Development; Disease; Energy Metabolism; Enzymes; Exercise; Exercise Tolerance; Exhibits; Genetic; Glucose; Goals; Heart Diseases; Heart failure; In Vitro; Knock-out; Knockout Mice; Lead; Limb structure; Manganese Superoxide Dismutase; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Mus; Muscle; Muscle Fibers; Nitric Oxide; Oxidative Stress; Pathway interactions; Patients; Performance; Peroxisome Proliferator-Activated Receptors; Phenotype; Physicians; Population; Public Health; Resistance; Role; Secondary to; Skeletal Muscle; Stress; Structure; Vasodilation; Vasodilator Agents; adenylyl cyclase type V; angiogenesis; base; glucose uptake; improved; in vivo; insulin sensitivity; novel strategies; pressure; response

DESCRIPTION (provided by applicant): Improving exercise tolerance, one of the major goals of physicians treating patients with cardiovascular disease, can be achieved either by improving cardiac output and blood flow to skeletal muscle, or by improving energy metabolism in skeletal muscle, or both. However, less is known regarding specific molecular pathways that might be approached therapeutically to improve exercise tolerance. In the past, we have demonstrated that the adenylyl cyclase type 5 (AC5) knockout (KO) mouse lives one third longer than wild type and is protected against aging induced cardiomyopathy, and the development of heart failure induced by either chronic catecholamine or pressure overload stress. The current project is based on these studies and our preliminary data demonstrating that AC5 KO mice exhibit increased exercise capacity. Our overall hypothesis is that AC5 is a critical enzyme affecting stress resistance and exercise capacity. The goal of this project is to examine mechanisms involved in AC5 inhibition, which could lead to a novel approach to improve exercise performance. There are two major hypotheses: HYPOTHESIS A: AC5 inhibition permits enhanced exercise performance due to improved limb blood flow through enhanced vasodilator mechanisms or angiogenesis, whereas improved cardiac function and cardiac output are less likely mechanisms. HYPOTHESIS B: AC5 inhibition permits enhanced exercise performance due to improved mitochondrial function and/or resistance to oxidative stress and/or improved glucose utilization. The implications for Public Health are clear: improving exercise tolerance will have broad significance for aging, heart disease, most other diseases and even for the young, healthy population.

描述（由申请人提供）：提高运动耐量是医生治疗心血管疾病患者的主要目标之一，可以通过改善心输出量和骨骼肌血流量，或通过改善骨骼肌能量代谢，或两者兼而有之来实现。然而，对于可以通过治疗来提高运动耐量的特定分子途径知之甚少。过去，我们已经证明，腺苷酸环化酶 5 型 (AC5) 敲除 (KO) 小鼠比野生型小鼠寿命长三分之一，并且可以预防衰老引起的心肌病以及慢性儿茶酚胺或压力超负荷引起的心力衰竭压力。当前的项目基于这些研究和我们的初步数据，表明 AC5 KO 小鼠表现出增强的运动能力。我们的总体假设是 AC5 是影响抗压能力和运动能力的关键酶。该项目的目标是研究 AC5 抑制的机制，这可能会产生一种提高运动表现的新方法。有两个主要假设： 假设 A：AC5 抑制可通过增强血管舒张机制或血管生成改善肢体血流，从而增强运动表现，而改善心功能和心输出量则不太可能是机制。假设 B：由于线粒体功能改善和/或氧化应激抵抗力和/或葡萄糖利用改善，AC5 抑制可以增强运动表现。这对公共健康的影响是显而易见的：提高运动耐量对于衰老、心脏病、大多数其他疾病，甚至对年轻健康人群都具有广泛的意义。