Thyroid hormone control of myocardial metabolism in aging

甲状腺激素对衰老过程中心肌代谢的控制

• 批准号: 8052810
• 负责人: Michael A Portman
• 金额: $ 19.21万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052810
• 关键词: Aging; Binding; Cardiac; Cardiac Myocytes; Cardiomyopathies; Carrier Proteins; Chronic; Data; Dominant-Negative Mutation; Energy Metabolism; Energy Supply; Exercise; Fatty Acids; Functional disorder; Future; Genes; Genetic Transcription; Heart; Human; Hypothyroidism; Laboratories; Ligand Binding; Measures; Mediating; Mediation; Metabolic; Metabolism; Molecular; Mutation; Myocardial; Myosin Heavy Chains; Nuclear Receptors; Nutritional; Pathway interactions; Phenotype; Plasma; Process; Rattus; Reporting; Resistance; Response Elements; Role; Sarcoplasmic Reticulum; Signal Pathway; Signal Transduction; Starvation; Stress; Syndrome; Testing; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Training; Transgenic Mice; Triiodothyronine; Ventricular Remodeling; aged; base; biological adaptation to stress; conditioning; fatty acid metabolism; glucose uptake; heart function; improved; mRNA Expression; mouse model; oxidation; public health relevance; receptor; receptor binding; response; senescence; uptake

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.

描述（由适用提供）：甲状腺马烯通过与其核接收器（TRS）结合来调节心脏功能。从经典上讲，配体结合的接收器又与响应元件结合并控制关键心脏基因的转录。三碘甲状腺素-TR结合的降低，例如在全身性甲状腺功能减退症，对甲状腺果综合症（RTH）或各种转基因小鼠模型中的某些耐药性中发生的抗性。在人类心脏失败中，还报道了TR配体结合能力的变化。尽管这种心脏功能障碍部分通过改变兴奋和转运蛋白的改变发生，但我们实验室的数据表明甲状腺马酮还介导心肌代谢的变化。甲状腺受体功能障碍可能会限制心脏在压力反应期间转移底物途径并提供足够的能量供应的能力。在这些压力期间，慢性或间歇性饥饿可能导致异常的补偿过程和/或心肌细胞损伤。来自其他实验室的最新数据表明，与甲状腺激素受体的表达升高和结合能力相关，衰老大鼠的运动训练促进了改善的心脏功能。这些年龄大鼠的运动条件改变了TR调控基因的mRNA表达，例如肌球蛋白重链α和β，以及肌浆网的mRNA表达，表明甲状腺激素介导。据推测，甲状腺介导的信号通路是通过运动调节回传感心脏功能触发的，其水平类似于年轻心脏中测得的水平。这些数据强烈暗示甲状腺受体失调参与与年龄中某些状态相关的心肌病，例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老化的大鼠心脏缺乏对不同营养条​​件的响应底物摄取的能力。特别是，增加的脂肪酸供应不会抑制葡萄糖的摄取，这表明心肌„氧化能力受衰老的限制，并且衰老的心脏氧化物的氧化物能力限制了对压力或运动的反应。这是，甲状腺同胞信号传导触发的心肌重塑的改变可能主要是由代谢的变化引起的。我们已经在转基因小鼠中充分表征了心肌代谢，该小鼠在Trtr¿1中表现出显着的阴性心脏选择性突变，并记录了衰老的非转基因同窝仔的心脏中心异常的脂肪酸代谢。我们将使用衰老的小鼠模型，该模型表现出血浆总T3水平的轻度降低，以测试甲状腺同种酮介导衰老心脏中代谢表型的主要假设。拟议的对PA-08-38（衰老中的甲状腺）的研究将建立进一步研究的基础，该研究将检查甲状腺作用的分子机制，并确定甲状腺果中的代谢作用是否可以修饰衰老的心肌病。 公共卫生相关性：该提案是对PA-08-308“衰老中的甲状腺”的回应。我们将评估甲状腺骑马在控制衰老心脏中使用底物（燃料）中的作用。这些研究将在未来进行更多详细的机械研究的背景数据。