MYOCARDIAL ADAPTATIONS TO ADVANCE AGE AND EXERCISE

心肌对高龄和运动的适应

• 批准号: 2859694
• 负责人: Russell L Moore
• 金额: $ 21万
• 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/2859694
• 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.

在高龄（AGE），心脏僵硬度增加，收缩持续时间延长，心肌舒张受损，心脏调节细胞Ca 2+负荷的能力受损。 肌膜（SL）和肌浆网（SR）Ca 2+处理过程中的年龄依赖性改变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AGE相关的心脏功能变化. 虽然TR已显示出改善老年心脏的SR功能，但关于TR对AGE中SL Ca 2+调节过程的影响知之甚少。 影响跨膜Ca ~（2+）运动的过程在调节心肌细胞Ca ~（2+）平衡和心肌收缩力的形成中非常重要。 细胞Ca 2+内流和外流途径之间存在的动态平衡的任何扰动预计会影响心肌调节细胞Ca 2+含量、SR Ca 2+负荷和最终心肌细胞收缩功能的能力。本提案的目的是确定AGE和TR+AGE对F1杂种大鼠模型中心脏细胞Ca 2+调节关键要素的影响。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是否或现在AGE和TR+AGE影响SL NaCa交换，Ca 2+流出的主要途径从心肌细胞。 这些技术也将被用来确定AGE和TR+AGE如何影响完整心肌细胞中SR、NaCa交换、肌膜Ca 2 + ATP酶（泵）和线粒体对胞质[Ca 2 +]调节的相对贡献。 为了了解AGE和TR+AGE如何影响整合的细胞Ca 2+调节，将在设计用于干扰细胞Ca 2+内流和/或外流的实验条件下评估Langendorf灌注心脏的LV收缩功能和起搏心脏细胞中的可释放SR Ca 2+负荷。 总的来说，从拟议的研究中得到的信息应该提供深入了解AGE的不利影响和TR对心脏细胞Ca 2+稳态的积极影响的细胞基础。 很大一部分美国人群将进入高龄，并在未来25年内面临年龄依赖性心功能降低的风险。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，特别是在使用并行药物干预的情况下。 后者的可能性在老年时增加。