Skeletal Muscle Basis for Improved Exercise Endurance in AC5 KO

描述（由申请人提供）：提高运动耐受性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来实现，或者通过改善骨骼肌的能量代谢来实现，或者两者兼而有之。然而，对于可能通过治疗来提高运动耐受性的特定分子途径，我们所知甚少。在过去，我们已经证明腺苷酸环化酶5型（AC5）敲除（KO）小鼠的寿命比野生型长三分之一，并且可以防止衰老引起的心肌病，以及慢性儿茶酚胺或压力过载应激引起的心力衰竭的发展。目前的项目是基于这些研究和我们的初步数据，证明AC5 KO小鼠表现出增加的运动能力。我们的总体假设是AC5是一种影响抗逆性和运动能力的关键酶。该项目的目标是研究AC5抑制的机制，这可能会导致一种改善运动表现的新方法。主要有两种假设：假设A: AC5抑制通过增强血管舒张机制或血管生成机制改善肢体血流量，从而提高运动表现，而改善心功能和心输出量则不太可能是机制。假设B: AC5抑制可以通过改善线粒体功能和/或抗氧化应激和/或改善葡萄糖利用来提高运动表现。这对公共卫生的影响是显而易见的：提高运动耐受性将对衰老、心脏病、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.