Deciphering a Regulatory Circuit for Myocardial Metabolism and Energy Homeostasis

描述（由申请人提供）：心脏需要高效的代谢来维持收缩性和泵功能所需的ATP水平。心脏代谢异常与肥胖、2型糖尿病和心力衰竭有关，这是主要的健康流行病。核激素受体及其共激活因子和共抑制因子通过调节参与能量稳态和线粒体功能的基因表达，在能量代谢的控制中发挥关键作用。核激素受体的转录控制是由中介体介导的，中介体是一个大的多蛋白复合物，通过与转录激活因子和抑制因子的关联，作为控制基因表达的枢纽。我们已经发现MED13/Thrap1是Mediator复合体的一个组成部分，作为心脏代谢的中央调节剂，并在此过程中影响小鼠的心脏功能和代谢稳态。因此，心脏MED13表达升高可增强心脏功能和代谢率，并赋予肥胖抵抗能力，而心脏MED13缺乏会导致心脏代谢降低，易患肥胖。MED13受microrna 208和378负调控，microrna 208和378控制应力依赖性心脏重塑和代谢。该项目的总体目标是确定MED13及其调控microrna控制代谢、能量稳态、线粒体生物发生、心脏应激反应和心脏和骨骼肌表型转换的精确机制。这些研究将为以前未被认识的横纹肌代谢和功能控制调控网络提供重要的新见解，并将为通过介质-微rna网络治疗代谢综合征和肌肉疾病提供机会。

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.