Division of Cardiology and Department of Pediatrics, University of Washington, and Seattle Children's Hospital Research Institute, Center for Developmental Therapeutics, Seattle, Washington, USA.
Am J Physiol Heart Circ Physiol. 2010 Sep;299(3):H868-75. doi: 10.1152/ajpheart.00931.2009. Epub 2010 Jul 2.
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.
衰老可能会引发底物氧化的转变，部分原因是胰岛素敏感性的变化。类似的转变也会发生在心脏肥大中，并可能导致收缩功能障碍。我们测试了这样一个假设，即衰老改变了底物的利用，并在提供多种底物时改变了小鼠心脏的胰岛素敏感性。通过左心室微尖压力传感器在体内测量控制（4-6 个月）和衰老（22-24 个月）小鼠的心脏功能。还通过使用含有（13）C 标记的游离脂肪酸（FFA）、乙酰乙酸盐、乳酸和未标记的葡萄糖的灌流液，在分离的工作心脏中测量心脏功能以及底物和柠檬酸循环（CAC）的补充分数。在体内，衰老小鼠的每搏量和心输出量减少，但压力发展得到维持。衰老分离心脏的收缩和舒张功能得到维持。胰岛素促使衰老心脏的收缩功能增加，从而提高心脏效率。FFA 和酮体通量存在，但在衰老心脏中明显受损。心肌底物利用的这些变化与循环脂质、甲状腺激素的变化以及过氧化物酶体增殖物激活受体（PPAR）alpha 和丙酮酸脱氢酶激酶（PDK）4 的蛋白表达减少相对应。胰岛素进一步抑制了衰老心脏中 FFA 的氧化。在衰老心脏中，胰岛素刺激的补料作用不存在。衰老的心脏通过利用多种底物来维持功能，表现出代谢可塑性。然而，脂肪酸氧化能力有限。胰岛素刺激的补料作用受损可能导致心脏效率升高，但也可能通过 CAC 中间产物的耗竭限制对急性应激的反应。
