Deciphering a Regulatory Circuit for Myocardial Metabolism and Energy Homeostasis

描述(申请人提供)：心脏需要高效的新陈代谢，以维持收缩和泵功能所需的三磷酸腺苷水平。心脏代谢异常与肥胖、2型糖尿病和心力衰竭有关，这些疾病代表着主要的健康流行病。核激素受体及其辅活化子和辅抑制子通过调节能量稳态和线粒体功能相关基因的表达，在能量代谢调控中发挥重要作用。核激素受体的转录调控是由介体介导的，介体是一种大型的多蛋白复合体，通过与转录激活因子和阻遏因子的结合发挥枢纽的作用，控制基因的表达。我们发现，MED13/ThRap1是介体复合体的一个组成部分，作为心脏代谢的中央调节因子，在这样做的过程中，影响小鼠的心脏功能和代谢稳态。因此，心脏中MED13的高表达增强了心脏功能和代谢率，并增强了对肥胖的抵抗力，而心脏中MED13的缺乏会导致心脏新陈代谢减弱和对肥胖的易感性。MED13受控制应激依赖的心脏重构和代谢的microRNAs208和378的负调控。该项目的总体目标是确定MED13及其调控的microRNAs控制新陈代谢、能量稳态、线粒体生物发生、心脏应激反应以及心肌和骨骼肌的表型转换的精确机制。这些研究将为以前未知的横纹肌代谢和功能调控网络提供重要的新见解，并将通过介体-microRNA网络为代谢综合征和肌肉疾病的治疗调控提供机会。

DESCRIPTION (provided by applicant): The heart requires highly efficient metabolism to maintain the levels of ATP needed for contractility and pump function. Aberrant cardiac metabolism is associated with obesity, type 2 diabetes and heart failure, which represent major health epidemics. Nuclear hormone receptors and their coactivators and corepressors play critical roles in the control of energy metabolism by regulating the expression of genes involved in energy homeostasis and mitochondrial function. Transcriptional control by nuclear hormone receptors is mediated by the Mediator, a large multiprotein complex that functions as a hub to control gene expression through association with transcriptional activators and repressors. We have discovered that MED13/Thrap1, a component of the Mediator complex, functions as a central regulator of cardiac metabolism and, in so doing, influences cardiac function and metabolic homeostasis in mice. Thus, elevated cardiac expression of MED13 enhances cardiac function and metabolic rate and confers resistance to obesity, whereas MED13 deficiency in the heart causes diminished cardiac metabolism and susceptibility to obesity. MED13 is negatively regulated by microRNAs 208 and 378, which control stress-dependent cardiac remodeling and metabolism. The overall goals of this project are to define the precise mechanisms whereby MED13 and the microRNAs that regulate it control metabolism, energy homeostasis, mitochondrial biogenesis, cardiac stress-responsiveness and phenotypic switching of cardiac and skeletal muscles. These studies will provide important new insights into a previously unrecognized regulatory network for the control of striated muscle metabolism and function, and will open opportunities for therapeutic modulation of metabolic syndromes and muscle diseases through the Mediator-microRNA network.