Metabolic Control by Myogenic MicroRNAs, Mediator and Myokines

描述（由申请人提供）：肥胖及相关疾病，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，骨骼肌是分泌肽激素和细胞因子的来源，被称为肌因子，以内分泌方式控制代谢、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，我们发现了一个肌肉特异性microRNAs家族（miRNAs）控制着全身能量稳态和肌纤维多样性。这些被称为myomir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最主要的靶标是Med13，它是Mediator复合体的一个组成部分，作为转录控制的调控中心。通过调节核激素受体信号传导，介导亚基涉及代谢的许多方面。然而，Med13和其他中介亚基在骨骼肌中的功能尚未被探索。我们的研究表明MyomiRs与Med13（可能还有其他介质亚基）一起在横条肌中建立了一个影响全身能量平衡和代谢的调节回路。我们已经发现了几个在肌纤维转换过程中受到调节的肌因子。该项目的总体目标是破译myomir和中介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广泛的初步工作基础，以及许多转基因小鼠，其中MyomiR-Mediator-Myokine通路已通过功能增益和功能丧失方法进行调节。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，作为使肥胖、糖尿病和代谢综合征的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.