MYOCARDIAL ADAPTATIONS TO ADVANCE AGE AND EXERCISE

在高龄（age）中，心脏的硬度增加，收缩持续时间延长，心肌松弛受损，心脏调节细胞Ca2+负荷的能力受损。年龄依赖性的改变在肌层（SL）和肌浆网（SR） Ca2+处理过程被认为有助于这些不希望的变化。耐力运动训练（TR）可以改善许多与年龄相关的心脏功能变化。虽然TR已被证明可以改善老年心脏的SR功能，但对于TR在老年中对SL Ca2+调节过程的影响知之甚少。影响跨细胞Ca2+运动的过程在调节心肌细胞Ca2+平衡和心脏收缩力发展中非常重要。在细胞Ca2+内流和外排途径之间存在的动态平衡中的任何扰动都可能影响心肌调节细胞Ca2+含量、SR Ca2+负荷并最终影响心肌收缩功能的能力。本提案的目的是确定在F1杂交大鼠模型中AGE和TR+AGE对心肌细胞Ca2+调节的关键因素的影响。荧光显微镜、快速溶液切换和全细胞电生理技术将被用于确定AGE和TR+AGE是否或现在影响SL NaCa交换，这是心肌细胞Ca2+外流的主要途径。这些技术还将用于确定AGE和TR+AGE如何影响SR、NaCa交换、肌层Ca2+ atp酶（泵）和线粒体对完整心肌细胞胞浆[Ca2+]调节的相对贡献。为了了解细胞内钙离子的综合调节如何受到AGE和TR+AGE的影响，Langendorf灌注心脏的左室收缩功能和有节奏的心肌细胞中可释放的SR Ca2+负荷将在旨在干扰细胞Ca2+内流和/或外排的实验条件下进行评估。总的来说，从拟议的研究中得到的信息应该提供对AGE不利影响的细胞基础和TR对心脏细胞Ca2+稳态的积极影响的见解。在未来25年内，很大一部分美国人口将进入高龄，并面临年龄依赖性心功能下降的风险。了解tr诱导的老年心脏功能适应的细胞过程，可能有助于制定预防和/或逆转心肌衰老的策略，特别是在使用平行药物干预的情况下。后者的可能性随着年龄的增长而增加。

In advanced age (AGE), the stiffness of the heart increases, contraction duration is prolonged, myocardial relaxation is impaired, and the ability of the heart to regulate cellular Ca2+ load is impaired. AGE- dependent alterations in sarcolemmal (SL) and sarcoplasmic reticular (SR) Ca2+ handling processes are thought to contribute to these undesirable changes. Endurance exercise training (TR) ameliorates many of these AGE- related functional changes in the heart. While TR has shown to improve SR function in the aged heart, little is known about the effects of TR on the SL Ca2+ regulatory processes in AGE. Processes that affect transarcolemmal Ca2+ movement are very important in the regulation of cardiocyte Ca2+ balance and cardiac contractile force development. Any perturbation in the dynamic equilibrium that exists between the cellular Ca2+ influx and efflux pathways would be expected to affect the ability of the myocardium to regulate cellular Ca2+ content, SR Ca2+ load, and ultimately cardiocyte contractile function. The objectives of this proposal are to determine the effects of AGE and TR+AGE on key elements of cardiocyte Ca2+ regulation in the F1 hybrid rat model. Fluorescence microscopy, rapid solution switching, and whole cell electrophysiologic techniques will be employed to determine whether or now AGE and TR+AGE affect SL NaCa exchange, the primary pathway of Ca2+ efflux from the cardiocyte. These techniques will also be exploited to determine how AGE and TR+AGE affect the relative contributions of the SR, NaCa exchange, the sarcolemmal Ca2+ ATPase (pump), and the mitochondria to cytosolic [Ca2+] regulation in intact cardiocytes. In order to gain an appreciation of how integrated cellular Ca2+ regulation is affected by AGE and TR+AGE, LV contractile function of Langendorf perfused hearts and releasable SR Ca2+ load in paced cardiocytes will be assessed under experimental conditions designed to perturb cellular Ca2+ influx and/or efflux. Collectively, the information resulting from the proposed studies should provide insights into the cellular basis of the adverse affect of AGE and the positive effects of TR on cellular Ca2+ homeostasis in the heart. A large portion of the US population will reach advanced age and be at risk of age-dependent reductions in cardiac function in the next 25 y. An understanding of the cellular processes that underlie TR-induced functional adaptations in the aged heart may prove useful in the development of strategies to prevent and/or reverse myocardial senescence, particularly in a setting where parallel pharmacological intervention is being used. The likelihood of the latter increases in advanced age.