title: Aging impairs myocardial fatty acid and ketone oxidation and modifies cardiac functional and metabolic responses to insulin in mice.
abstract: Aging presumably initiates shifts in substrate oxidation mediated in part by changes in insulin sensitivity. Similar shifts occur with cardiac hypertrophy and may contribute to contractile dysfunction. We tested the hypothesis that aging modifies substrate utilization and alters insulin sensitivity in mouse heart when provided multiple substrates. In vivo cardiac function was measured with microtipped pressure transducers in the left ventricle from control (4-6 mo) and aged (22-24 mo) 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 (13)C-labeled free fatty acids (FFA), acetoacetate, lactate, and unlabeled glucose. Stroke volume and cardiac output were diminished in aged mice in vivo, but pressure development was preserved. Systolic and diastolic functions were maintained in aged isolated hearts. Insulin prompted an increase in systolic function in aged hearts, resulting in an increase in cardiac efficiency. FFA and ketone flux were present but were markedly impaired in aged hearts. These changes in myocardial substrate utilization corresponded to alterations in circulating lipids, thyroid hormone, and reductions in protein expression for peroxisome proliferator-activated receptor (PPAR)alpha and pyruvate dehydrogenase kinase (PDK)4. Insulin further suppressed FFA oxidation in the aged. Insulin stimulation of anaplerosis in control hearts was absent in the aged. The aged heart shows metabolic plasticity by accessing multiple substrates to maintain function. However, fatty acid oxidation capacity is limited. Impaired insulin-stimulated anaplerosis may contribute to elevated cardiac efficiency, but may also limit response to acute stress through depletion of CAC intermediates.
authors.affiliation: Division of Cardiology and Department of Pediatrics, University of Washington, and Seattle Children's Hospital Research Institute, Center for Developmental Therapeutics, Seattle, Washington, USA.
authors.forename: Outi M
authors.initials: OM
authors.lastname: Hyyti
authors.forename: Dolena
authors.initials: D
authors.lastname: Ledee
authors.forename: Xue-Han
authors.initials: XH
authors.lastname: Ning
authors.forename: Ming
authors.initials: M
authors.lastname: Ge
authors.forename: Michael A
authors.initials: MA
authors.lastname: Portman
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002302:Cardiac Output / Q000187:drug effects / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007659:Ketones / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology
chemical_list: D005227:Fatty Acids; D007328:Insulin; D007659:Ketones; D047493:PPAR alpha