Abstract 11246: Aging Impairs Myocardial Fatty Acid and Ketone Oxidation and Modifies Functional and Anaplerotic Response to Insulin
Aging presumably initiates shifts in substrate oxidation mediated in part by changes in insulin response. Fatty acid oxidation (FAO) is putatively impaired in aged hearts, due to a generalized decrease in myocardial oxygen consumption (MVO) and function. It is unknown if the aged heart maintains flexibility to access alternative substrate sources. We tested the hypothesis that aging modifies substrate utilization and alters insulin response in mouse heart, when provided multiple substrates.
Methods: In vivo cardiac function was measured using microtipped pressure transducers in the left ventricle from control (4–6 months, n = 8)) and aged (22–24 months, n = 7)) mice. Cardiac function was also measured in isolated working hearts along with substrate and anaplerotic fractional contributions to the citric acid cycle (CAC) by using perfusate containing 13carbon labeled free fatty acids (FFA), acetoacetate, lactate, and unlabeled glucose. Fractional contributions were determined with magnetic resonance spectroscopy.
Results: Stroke volume and cardiac output were diminished in aged mice in vivo but pressure development was preserved. Systolic and diastolic functions were also maintained in aged isolated hearts. Insulin prompted an increase in systolic function in aged hearts with maintained MVO resulting in increased cardiac efficiency (power/MVO). FFA and ketone flux were both markedly impaired in aged hearts. These changes in myocardial substrate utilization corresponded to alterations in circulating lipids and thyroid hormone. Marked reductions in protein expression in age hearts occurred for PPARα (20% of control) and pyruvate dehydrogenase kinase-4 without changes in mCPT-I, malonyl-CoA decarboxylase, or AKT. Insulin further suppressed FAO in the aged. Insulin also repressed anaplerosis in aged hearts, but not in control.
Conclusions: FAO and ketone oxidation capacities are limited in aged heart. However, aged heart shows metabolic plasticity by accessing multiple substrates, which maintains function and increases efficiency. Impaired anaplerosis response to insulin to may contribute to elevated cardiac efficiency, but may also limit the capability to response to acute stress by preventing CAC intermediate depletion.
- © 2010 by American Heart Association, Inc.