Thyroid hormone control of myocardial metabolism in aging

描述(申请人提供)：甲状腺激素通过与其核受体(TRs)结合来调节心脏功能。传统上，配体结合的受体反过来与反应元件结合，并控制关键心脏基因的转录。三碘甲腺原氨酸-三碘甲状腺原氨酸结合减少，如全身性甲状腺功能减退、甲状腺激素综合征(RTH)的某些抵抗，或各种转基因小鼠模型，都会对心脏功能产生不利影响。据报道，在衰竭的人类心脏中，也有受体配体结合能力的变化。虽然这种心功能障碍的发生部分是通过兴奋收缩和运输蛋白的改变，但我们实验室的数据表明，甲状腺激素也介导了心肌能量代谢的变化。甲状腺受体功能障碍可能会限制心脏在应激反应中转移底物途径和提供足够能量供应的能力。在这些应激期内，慢性或间歇性的能量饥饿可能会导致异常的代偿过程和/或心肌细胞损伤。来自其他实验室的最新数据表明，老年大鼠的运动训练促进了心功能的改善，这与甲状腺激素受体的表达和结合能力增加有关。这些老年大鼠的运动条件调节改变了tr调节基因的mRNA表达，如肌球蛋白重链α和β，以及肌浆网，提示甲状腺激素的调节。据推测，运动条件下触发的甲状腺介导的信号通路使衰老的心脏功能恢复到与年轻心脏相似的水平。这些数据强烈暗示甲状腺受体失调参与了与老年人某些状态相关的心肌病，如亚临床甲状腺功能减退症。代谢信号通路的变化可能解释了为什么衰老的大鼠心脏缺乏改变底物摄取的能力，以应对不同的营养条件。特别是，增加脂肪酸供应并不会抑制葡萄糖的摄取，这表明心肌的氧化能力受到衰老的限制，衰老心脏的底物氧化能力限制了对压力或运动的反应。因此，甲状腺激素信号在老年心脏中引发的心肌重构的改变可能主要是由代谢的变化引起的。我们已经对一只转基因小鼠的心肌代谢进行了充分的表征，该转基因小鼠在tré1中表达了显性负心脏选择突变，并记录了老年非转基因小鼠心脏中脂肪酸代谢的异常。我们将使用一个衰老的小鼠模型，该模型显示血浆总T3水平轻微下降，以检验甲状腺激素介导衰老心脏代谢表型的基本假设。针对PA-08-38(甲状腺在衰老中的作用)的拟议研究将为进一步的研究奠定基础，这些研究将探讨甲状腺作用的分子机制，并确定甲状腺激素的代谢作用是否可以改变衰老的心肌病。 公共卫生相关性：本提案是对PA-08-308“老龄化中的甲状腺”的回应。我们将评估甲状腺激素在控制老化心脏的底物(燃料)使用方面的作用。这些研究将作为未来更详细的机制研究的背景数据。

DESCRIPTION (provided by applicant): Thyroid hormone regulates cardiac function through binding to its nuclear receptors (TRs). Classically, the ligand bound receptors in turn bind to response elements and control transcription of key cardiac genes. A decrease in triiodothyronine-TR binding, such as occurs in systemic hypothyroidism, certain resistance to thyroid hormone syndromes (RTH), or in various transgenic mouse models adversely effects cardiac function. Changes in TR ligand binding capacity have also been reported in failing human hearts. Although, this cardiac dysfunction occurs in part through alterations in excitation-contraction and transport proteins, the data from our laboratory indicate that thyroid hormone also mediates changes in myocardial energy metabolism. Thyroid receptor dysfunction may limit the heart's ability to shift substrate pathways and provide adequate energy supply during stress responses. Chronic or intermittent energy starvation during these stress periods could contribute to abnormal compensatory processes and/or cardiomyocyte damage. Recent data from other laboratories indicate that exercise training in aged rats promoted improved cardiac function in association with elevated expression and binding capacity of thyroid hormone receptors. Exercise conditioning in these aged rats alters the mRNA expression for TR regulated genes such as myosin heavy chain alpha and beta, and sarcoplasmic reticulum in a manner suggesting mediation by thyroid hormone. Presumably, thyroid mediated signaling pathways triggered by exercise conditioning return senescent heart function to levels similar to those measured in much younger hearts. These data strongly imply that thyroid receptor dysregulation participates in cardiomyopathy associated with some states in the aged, such as subclinical hypothyroidism. Changes in metabolic signaling pathways might explain why the aging rat heart lacks the ability to modify substrate uptake in response to varying nutritional conditions. In particular, increasing fatty acid supply does not inhibit glucose uptake, suggesting that the myocardial ¿-oxidation capability is limited by aging, and that the aging heart's substrate oxidative capacity restricts responses to stress or exercise. Thus, alterations in myocardial remodeling triggered by thyroid hormone signaling in aged hearts may be caused primarily by changes in metabolism. We have fully characterized myocardial metabolism in a transgenic mouse expressing a dominant negative cardiac selective mutation in TR¿1 and documented abnormal fatty acid metabolism in heart of aged non-transgenic littermates. We will use an aging mouse model, which manifests mild reductions in plasma total T3 levels to test the primary hypothesis that thyroid hormone mediates the metabolic phenotype in the aging heart. The proposed studies in response to PA-08-38 (Thyroid in Aging) will establish the basis for further studies, which would examine the molecular mechanisms of thyroid action, and determine if metabolic action by thyroid hormone can modify the cardiomyopathy of aging. PUBLIC HEALTH RELEVANCE: This proposal is in response to PA-08-308 "Thyroid in Aging". We will evaluate thyroid hormone's role in controlling substrate (fuel) use in the aging heart. These studies will serve as background data for more elaborate mechanistic studies in the future.