Role of estrogen-related receptors in cardiac and skeletal muscle

描述（由申请人提供）：适当调节参与能量（ATP）生成的细胞代谢程序对正常组织发育和体内平衡至关重要。心脏和慢收缩骨骼肌中ATP的产生主要涉及脂肪酸和葡萄糖在线粒体内的氧化代谢。线粒体的能力！心脏和骨骼肌中ATP的产生和能量底物的选择受到发育、生理和环境线索的调节，这些线索发出参与这些过程的酶水平的协调变化的信号。适当调节的扰动导致线粒体代谢和底物选择的变化，这些变化与心脏和骨骼肌胰岛素抵抗和糖尿病、心力衰竭以及与年龄相关的肌肉功能下降有关。核受体（NR）转录因子及其共激活因子PGC-1a通过协调代谢酶基因表达的变化，在调节骨骼肌、心脏、棕色脂肪和肝脏的能量代谢中发挥核心作用。雌激素相关受体（ERR），ERRa和ERRg，由于它们在心脏和骨骼肌中的高表达以及它们对增加能量代谢的生理线索的响应性，已经被认为是心脏和骨骼肌中的重要代谢调节剂。为了了解肌肉中ERRs下游的广泛调控程序，我们建议使用ERRa和ERRg功能获得和丧失的体外细胞模型和遗传修饰小鼠模型。我们将分析这些模型与基因表达谱结合染色质免疫沉淀，以确定ERRs的靶基因。基于迄今为止确定的基因靶点，我们提出ERRs是心脏和骨骼肌能量代谢的重要激活剂，在肌细胞代谢程序的发育开关中发挥特别重要的功能。我们使用ERR亚型通过过表达选择性激活或通过基因靶向或小干扰RNA抑制的模型来评估代谢的调节。心肌和骨骼肌中ERR功能的表征对疾病状态具有重要意义，包括心力衰竭和心肌缺血、2型糖尿病和肥胖。我们的研究结果将阐明ERRs作为与代谢失调相关的广泛人类疾病的治疗靶点的潜力。

DESCRIPTION (provided by applicant): Appropriate regulation of cellular metabolic programs involved in energy (ATP) generation is essential for normal tissue development and homeostasis. ATP generation in heart and slow-twitch skeletal muscle involves primarily oxidative metabolism of fatty acids and glucose within the mitochondrion. The capacity for mitochondria! ATP generation and the selection of energy substrates in heart and skeletal muscle is regulated by developmental, physiological, and environmental cues that signal coordinated changes in the levels of enzymes involved these processes. Perturbations of appropriate regulation lead to changes in mitochondrial metabolism and substrate selection linked to heart and skeletal muscle insulin resistance and diabetes, heart failure and age-related declines in muscle function. Nuclear receptor (NR) transcription factors and their coactivator, PGC-1a, play a central role in regulating energy metabolism in skeletal muscle, heart, brown adipose and liver, by coordinating changes in metabolic enzyme gene expression. The estrogen-related receptors (ERR), ERRa and ERRg, have been implicated as important metabolic regulators in heart and skeletal muscle, due to their high expression in these tissues and their responsiveness to physiologic cues that increase energy metabolism. In order to understand the broad regulatory program downstream of ERRs in muscle, we propose using in vitro cell models and genetically-modified mouse models of ERRa and ERRg gain- and loss-of-function. We will analyze these models with gene expression profiling coupled with chromatin immunoprecipitation to identify target genes for ERRs. Based upon gene targets identified to date, we propose that ERRs are essential activators of heart and skeletal muscle energy metabolism that play particularly important function in developmental switches in myocyte metabolic programs. We assess the regulation of metabolism using models in which ERR isoforms are selectively activated by overexpression or inhibited by gene targeting or small-interfering RNA. The characterization of ERR function in cardiac and skeletal muscle has important implications for disease states, including heart failure and myocardial ischemia, type 2 diabetes, and obesity. Our findings will elucidate the potential for ERRs as therapeutic targets for widespread human diseases associated with metabolic dysregulation.