Metabolic Control by Myogenic MicroRNAs, Mediator and Myokines

描述(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递引起的全身性异常。骨骼肌在控制全身新陈代谢、能量平衡和胰岛素敏感性等方面起着核心作用。此外，骨骼肌是分泌多肽激素和细胞因子的来源，这些激素和细胞因子被称为肌肉因子，以内分泌方式发挥作用，控制新陈代谢、炎症和其他过程。虽然肌动蛋白的重要性越来越明显，但关于这些因素的身份、控制它们表达的机制以及它们的作用机制，仍有许多需要了解。最近，我们发现一组肌肉特异的microRNAs(MiRNAs)控制着全身的能量平衡和肌纤维的多样性。这些被称为myomiRs的miRNAs通过抑制一系列转录因子的表达来发挥作用，这些转录因子调节涉及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Med13，它是中介复合体的一个组成部分，充当转录调控的调控中心。通过调节核激素受体信号，中介亚基参与了代谢的许多方面。然而，Med13和其他中介亚基在骨骼肌中的功能还没有被探索。我们的研究表明，myomiRs和Med13(可能还有其他调节亚基)一起在横纹肌中建立调节电路，影响全身能量平衡和新陈代谢。我们已经发现了几种在肌纤维转换过程中受到调节的肌动蛋白。这个项目的总体目标是破译myomiRs和Mediator亚基控制myokine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对活动和疾病的适应中的作用。该项目基于我们团队以及大量转基因小鼠的广泛基础上的前期工作，在这些转基因小鼠中，MyomiR-Mediator-myokine通路已经通过获得和失去功能的方法进行了调节。最终，我们希望利用这些洞察力来开发新的策略，以治疗性地调节肌细胞因子信号，作为肥胖、糖尿病和代谢综合征环境下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.