Outi M. Hyyti

Aging impairs myocardial fatty acid and ketone oxidation and modifies cardiac functional and metabolic responses to insulin in mice

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.

Molecular mechanisms of cross-talk between thyroid hormone and peroxisome proliferator activated receptors: focus on the heart.

Thyroid hormone receptors (TR) and peroxisome proliferator activated receptors (PPAR) regulate cardiac metabolism. Numerous studies have examined TR and PPAR function since PPAR was first discovered in the early 1990s, however few have evaluated TR and PPAR interactions. Although ligands for these members of the nuclear steroid receptor family are under evaluation for treatment of congestive heart failure and various metabolic diseases, their interactions have not been investigated in detail in heart. These interactions are remarkably complicated. Nevertheless, their identification and elucidation is extremely important for further development of specific drugs. We review here the fundamental ways TRs and PPARs are regulated and how their cross-talk patterns mediate transcription of their target genes.

Time‐courses of perfusion and phosphocreatine in rat leg during low‐level exercise and recovery

To develop a noninvasive protocol for measuring local perfusion and metabolic demand in muscle tissue with sufficient sensitivity and time resolution to monitor kinetics at the onset of low‐level exercise and during recovery.