Skeletal Muscle Basis for Improved Exercise Endurance in AC5 KO

描述(申请人提供)：提高运动耐力，这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流向骨骼肌的血液，或者通过改善骨骼肌的能量代谢，或者两者兼而有之。然而，对于可以通过治疗来提高运动耐量的特定分子途径，我们知之甚少。过去，我们已经证明，腺苷环化酶5(AC5)基因敲除(KO)小鼠的寿命比野生型长三分之一，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应激导致的心力衰竭。目前的项目是基于这些研究和我们的初步数据表明，AC5KO小鼠表现出更强的运动能力。我们的总体假设是，AC5是一种影响抗应激和运动能力的关键酶。这个项目的目标是研究AC5抑制的机制，这可能会导致一种新的方法来提高运动成绩。有两个主要的假设：假设A：AC5抑制可以通过增强的血管扩张机制或血管生成改善肢体血流，从而提高运动能力，而改善心功能和心输出量的可能性较小。假设B：抑制AC5可以通过改善线粒体功能和/或抵抗氧化应激和/或改善葡萄糖利用来提高运动能力。这对公共健康的影响是明确的：提高运动耐量将对老龄化、心脏病和大多数其他疾病，甚至对年轻、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.