Cardiac Mitochondrial Function and Exertional Tolerance in a Rat Model of Pressure-Overload Induced Heart Failure

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Heart failure (HF) is characterized by the inability of the heart to provide adequate cardiac output to meet their body’s demand for fuel and oxygen, particularly during periods of exertion. In fact, a hallmark characteristic of HF is exertional intolerance where performing activities brings about, or exacerbates, symptoms of dyspnea and/or fatigue. This exercise intolerance has been attributed to altered cardiac and skeletal muscle function. The myocardium of the heart is reliant upon cardiac mitochondria to generate sufficient ATP to fuel this highly metabolically active tissue. Therefore, reduced mitochondrial ATP production may play a role in myocardial dysfunction and contribute to reduced cardiac output in HF. Mitochondria react to intracellular signals to respond to energetic demands, and therefore, mitochondrial function is a product of both the mitochondria itself and the environment in which it resides. Intracellular Ca2+ and Na+ are of particular interest as they play a role in regulating mitochondrial function and the intracellular concentrations are elevated in ventricular myocytes in HF. Therefore, a goal of these investigations was to evaluate how altered Na+ and Ca2+ can impact the ability of cardiac mitochondria to respond to an increase in demand in mitochondria isolated from young healthy rat hearts, as well as rats with pressure-overload induced HF. A second goal of these investigations was to determine if pressure-overload induced heart failure altered exercise capacity, as well as in vivo and ex vivo skeletal muscle strength.

In the first study, mitochondria were isolated from the ventricular tissue of young, healthy male rats, and oxygen consumption and mitochondrial activation by Ca2+ was assessed in the presence of elevated Na+ to mimic the cellular environment of HF. Ca2+ effectively activated mitochondrial ATP production, despite elevated Na+, suggesting that the ionic conditions of HF ventricular myocytes alone are not sufficient to disrupt mitochondrial function. In the second study, mitochondrial function was assessed under the same ionic conditions as the previous study, however, mitochondria were isolated from male rats with pressure-overload induced hypertrophy or sham-operated controls. Ca2+ was able to activate mitochondrial function regardless of Na+ concentration in both HF and sham mitochondria; however, failing mitochondria exhibited depolarized mitochondrial membrane values across these respiration rates, implicating an impaired potential for ATP production in failing ventricular mitochondria. In the third study, HF and sham male and female rats were evaluated for their exertional tolerance, and the results indicated that HF rats tolerated treadmill running and showed no deficits in grip exercise; however, solei muscle from female heart failure rats exhibited diminished contractile capacity, suggesting female skeletal muscle may respond differently than male skeletal muscle to heart failure. These findings indicate that failing mitochondria may be intrinsically dysfunctional regardless of an altered ionic environment and that there may be sexual dimorphism in the skeletal muscle function and its role in exercise intolerance in HF.