MYOCARDIAL ADAPTATIONS TO ADVANCE AGE AND EXERCISE

心肌对高龄和运动的适应

• 批准号: 6168849
• 负责人: Russell L Moore
• 金额: $ 21.63万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6168849
• 关键词: action potentials; age difference; aging; animal old age; calcium flux; calcium indicator; cardiac myocytes; cell senescence; charge coupled device camera; exercise; heart contraction; laboratory rat; muscle strength; myocardium; sarcolemma; voltage /patch clamp

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.

高龄时，心脏的僵硬程度增加，收缩持续时间延长，心肌松弛受损，心脏调节细胞钙负荷的能力受损。肌膜(SL)和肌浆网(SR)钙处理过程中年龄相关的变化被认为是导致这些不良变化的原因。耐力运动训练可以改善心脏中许多与年龄相关的功能变化。虽然TR已被证明可以改善老年心脏的SR功能，但对老年心脏SL钙调节过程的影响却知之甚少。影响跨膜钙运动的过程在调节心肌细胞钙平衡和心肌收缩力发育过程中起着非常重要的作用。细胞内钙内流和外流通路之间的动态平衡的任何扰动都可能影响心肌调节细胞内钙含量、肌浆网钙负荷，最终影响心肌细胞收缩功能。本研究的目的是确定AGE和Tr+AGE对F1杂交大鼠心肌细胞钙调节关键成分的影响。荧光显微镜、快速溶液转换和全细胞电生理技术将被用来确定AGE和TR+AGE是否影响心肌细胞钙外流的主要途径SL NACA交换。这些技术还将被用来确定AGE和TR+AGE如何影响SR、NACA交换、肌膜Ca~(2+)ATPase(泵)和线粒体对完整心肌细胞胞浆[Ca~(2+)]调节的相对贡献。为了了解完整的细胞内钙调节如何受年龄和tr+年龄的影响，我们将在干扰细胞内钙内流和/或外流的实验条件下，评估朗恩多夫灌流心脏的左心室收缩功能和起搏心肌细胞内可释放的肌浆网钙负荷。综上所述，这些拟议研究的信息应能深入了解AGE的不利影响的细胞学基础，以及tr对心脏细胞内钙稳态的积极影响。在接下来的25年里，很大一部分美国人将步入高龄，并面临年龄相关性心功能减退的风险。了解在老年心脏中由TR诱导的功能适应背后的细胞过程可能被证明有助于制定预防和/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。