Metabolic Control by Myogenic MicroRNAs, Mediator and Myokines

描述（由申请人提供）：肥胖和相关疾病，包括代谢综合征、2型糖尿病和高脂血症，是由异常代谢、能量利用和组织间信号传导引起的全身性异常。骨骼肌在控制全身代谢、能量稳态和胰岛素敏感性方面起着核心作用。此外，骨骼肌作为分泌的肽激素和细胞因子的来源，称为肌因子，其以内分泌方式起作用以控制代谢、炎症和其他过程。虽然肌因子的重要性越来越明显，但关于这些因子的身份、控制其表达的机制及其作用机制仍有许多有待了解。最近，我们发现一个家族的肌肉特异性microRNAs（miRNAs）控制系统能量稳态和肌纤维的多样性。这些称为MyomiRs的miRNA通过抑制一系列转录因子的表达来发挥作用，这些转录因子调节参与代谢控制和纤维类型转换的基因程序。MyomiRs最主要的靶标之一是Med 13，它是介体复合物的一个组分，充当转录控制的调控中心。介体亚基通过调节核激素受体信号转导参与代谢的许多方面。然而，Med 13和其他Mediator亚基在骨骼肌中的功能尚未被探索。我们的研究表明，MyomiRs与Med 13（可能还有其他中介子亚基）一起在横纹肌中建立了一个调节回路，影响全身能量平衡和代谢。我们已经发现了几种在肌纤维转换过程中受到调节的肌因子。该项目的总体目标旨在破译MyomiRs和Mediator亚基控制肌因子产生的上游机制，阐明这些分子的作用机制，并确定它们在骨骼肌适应活动和疾病中的作用。该项目是基于我们小组的初步工作的广泛基础，以及许多转基因小鼠，其中MyomiR-Mediator-Myokine途径已通过获得和丧失功能的方法进行调节。最终，我们希望利用这些见解来开发新的策略，以治疗性地调节肌因子信号传导，作为在肥胖、糖尿病和代谢综合征环境中使代谢正常化的一种手段。

DESCRIPTION (provided by applicant): Obesity and associated disorders, including metabolic syndrome, type 2 diabetes, and hyperlipidemia, are systemic abnormalities that result from aberrant metabolism, energy utilization and signaling between tissues. Skeletal muscle plays a central role in the control of whole-body metabolism, energy homeostasis and insulin sensitivity. In addition, skeletal muscle serves as a source of secreted peptide hormones and cytokines, referred to as myokines that act in an endocrine manner to control metabolism, inflammation and other processes. While the importance of myokines is becoming increasingly apparent, much remains to be learned about the identities of these factors, the mechanisms that control their expression and their mechanisms of action. Recently, we discovered that a family of muscle-specific microRNAs (miRNAs) control systemic energy homeostasis and myofiber diversity. These miRNAs, called MyomiRs, exert their actions by repressing the expression of a collection of transcription factors that regulate gene programs involved in metabolic control and fiber type switching. Among the most dominant targets of the MyomiRs is Med13, a component of the Mediator complex, which acts as a regulatory hub for transcriptional control. Mediator subunits have been implicated in numerous aspects of metabolism through regulation of nuclear hormone receptor signaling. However, the functions of Med13 and other Mediator subunits in skeletal muscle have not been explored. Our studies suggest that MyomiRs together with Med13 (and possibly other Mediator subunits) establish a regulatory circuit in striated muscle that influences systemic energy balance and metabolism. We have discovered several myokines that are regulated during myofiber switching. The overall goals of this project are designed to decipher the upstream mechanisms whereby MyomiRs and Mediator subunits govern myokine production, to elucidate the mechanisms of action of these molecules, and to define their roles in skeletal muscle adaptations to activity and disease. The project is based on an extensive foundation of preliminary work from our group, as well as numerous genetically modified mice in which the MyomiR-Mediator-Myokine pathways have been modulated through gain- and loss-of-function approaches. Ultimately, we hope to use these insights to develop new strategies to therapeutically modulate myokine signaling as a means of normalizing metabolism in settings of obesity, diabetes and metabolic syndrome.