Hyyti Outi M, Olson Aaron K, Ge Ming, Ning Xue-Han, Buroker Norman E, Chung Youngran, Jue Thomas, Portman Michael A
Children's Hospital and Regional Medical Center MSW 4841, 4800 Sand Point Way NE, Seattle, WA 98105, USA.
Am J Physiol Endocrinol Metab. 2008 Aug;295(2):E420-7. doi: 10.1152/ajpendo.90329.2008. Epub 2008 Jun 3.
Dominant-negative thyroid hormone receptors (TRs) show elevated expression relative to ligand-binding TRs during cardiac hypertrophy. We tested the hypothesis that overexpression of a dominant-negative TR alters cardiac metabolism and contractile efficiency (CE). We used mice expressing the cardioselective dominant-negative TRbeta(1) mutation Delta337T. Isolated working Delta337T hearts and nontransgenic control (Con) hearts were perfused with (13)C-labeled free fatty acids (FFA), acetoacetate (ACAC), lactate, and glucose at physiological concentrations for 30 min. (13)C NMR spectroscopy and isotopomer analyses were used to determine substrate flux and fractional contributions (Fc) of acetyl-CoA to the citric acid cycle (CAC). Delta337T hearts exhibited rate depression but higher developed pressure and CE, defined as work per oxygen consumption (MVo(2)). Unlabeled substrate Fc from endogenous sources was higher in Delta337T, but ACAC Fc was lower. Fluxes through CAC, lactate, ACAC, and FFA were reduced in Delta337T. CE and Fc differences were reversed by pacing Delta337T to Con rates, accompanied by an increase in FFA Fc. Delta337T hearts lacked the ability to increase MVo(2). Decreases in protein expression for glucose transporter-4 and hexokinase-2 and increases in pyruvate dehydrogenase kinase-2 and -4 suggest that these hearts are unable to increase carbohydrate oxidation in response to stress. These data show that Delta337T alters the metabolic phenotype in murine heart by reducing substrate flux for multiple pathways. Some of these changes are heart rate dependent, indicating that the substrate shift may represent an accommodation to altered contractile protein kinetics, which can be disrupted by pacing stress.
在心脏肥大过程中，显性负性甲状腺激素受体（TRs）相对于配体结合型TRs呈现出表达升高的现象。我们检验了这样一个假说，即显性负性TR的过表达会改变心脏代谢和收缩效率（CE）。我们使用了表达心脏选择性显性负性TRβ(1)突变体Δ337T的小鼠。将分离的工作状态下的Δ337T心脏和非转基因对照（Con）心脏用生理浓度的（13）C标记的游离脂肪酸（FFA）、乙酰乙酸（ACAC）、乳酸和葡萄糖灌注30分钟。采用（13）C核磁共振波谱法和同位素异构体分析来确定底物通量以及乙酰辅酶A对柠檬酸循环（CAC）的分数贡献（Fc）。Δ337T心脏表现出心率降低，但舒张末压和CE更高，CE定义为每耗氧量（MVo(2)）所做的功。来自内源性来源的未标记底物Fc在Δ337T心脏中更高，但ACAC Fc更低。Δ337T心脏中通过CAC、乳酸、ACAC和FFA的通量降低。通过将Δ337T心脏起搏至Con心脏的速率，CE和Fc差异得以逆转，同时FFA Fc增加。Δ337T心脏缺乏增加MVo(2)的能力。葡萄糖转运蛋白4和己糖激酶2的蛋白表达降低，丙酮酸脱氢酶激酶2和4的表达增加，这表明这些心脏无法在应激时增加碳水化合物氧化。这些数据表明，Δ337T通过降低多种途径的底物通量来改变小鼠心脏的代谢表型。其中一些变化是心率依赖性的，表明底物转移可能代表了对收缩蛋白动力学改变的一种适应，而这种适应可被起搏应激所破坏。
