Role of estrogen-related receptors in cardiac and skeletal muscle

描述（由申请人提供）：适当调节细胞代谢程序涉及能量（ATP）的产生是正常组织发育和体内平衡所必需的。心脏和慢缩骨骼肌的ATP生成主要涉及线粒体内脂肪酸和葡萄糖的氧化代谢。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、生理和环境信号的调节，这些信号表明参与这些过程的酶水平发生了协调的变化。适当调控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、心力衰竭和与年龄相关的肌肉功能下降有关。核受体（NR）转录因子及其辅激活因子PGC-1a通过协调代谢酶基因表达的变化，在骨骼肌、心脏、棕色脂肪和肝脏的能量代谢调节中发挥核心作用。雌激素相关受体（ERR）， ERRa和ERRg，在心脏和骨骼肌中被认为是重要的代谢调节因子，因为它们在这些组织中高表达，并且对增加能量代谢的生理信号有反应。为了了解erg在肌肉中下游的广泛调控程序，我们建议使用体外细胞模型和转基因小鼠模型来研究ERRa和ERRg的功能获得和功能丧失。我们将用基因表达谱结合染色质免疫沉淀来分析这些模型，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必要激活因子，在肌细胞代谢程序的发育开关中起着特别重要的作用。我们使用ERR异构体通过过度表达选择性激活或被基因靶向或小干扰RNA抑制的模型来评估代谢调节。心脏和骨骼肌ERR功能的表征对疾病状态有重要意义，包括心力衰竭和心肌缺血、2型糖尿病和肥胖。我们的发现将阐明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.