Skeletal Muscle Basis for Improved Exercise Endurance in AC5 KO

描述（由申请人提供）：改善运动耐量是医生治疗心血管疾病患者的主要目标之一，可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来实现。然而，关于可能在治疗上接近以改善运动耐量的特定分子途径知之甚少。在过去，我们已经证明，腺苷酸环化酶5型（AC 5）敲除（KO）小鼠的寿命比野生型长三分之一，并防止衰老诱导的心肌病，以及慢性儿茶酚胺或压力超负荷应激诱导的心力衰竭的发展。目前的项目是基于这些研究和我们的初步数据表明，AC 5基因敲除小鼠表现出增加的运动能力。我们的总体假设是，AC 5是影响应激抵抗力和运动能力的关键酶。该项目的目标是研究AC 5抑制的机制，这可能会导致一种新的方法来改善运动表现。有两个主要假设：假设A：AC 5抑制允许增强运动表现，这是由于通过增强血管扩张机制或血管生成改善肢体血流，而改善心脏功能和心输出量是不太可能的机制。假设B：由于改善的线粒体功能和/或对氧化应激的抗性和/或改善的葡萄糖利用，AC 5抑制允许增强的运动表现。对公共卫生的影响是明确的：提高运动耐量将对衰老，心脏病，大多数其他疾病，甚至年轻，健康的人群具有广泛的意义。

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.