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.
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