Examining the role of succinate-SUCNR1 signaling in skeletal muscle remodeling following exercise.

摘要 运动被认为是多种代谢性疾病最有效的预防措施之一 包括糖尿病、肥胖症和心血管疾病。然而，运动的需求导致大量的 对骨骼肌的机械和能量应力。肌肉必须经历一个广泛的重塑过程， 为了满足这些要求。该过程包括神经营养信号传导、血管生成、细胞外 基质（ECM）重塑和肥大。重塑过程在运动后迅速发生， 这取决于多种非实质驻留细胞的活性。然而，不知道如何锻炼 骨骼肌与这些细胞沟通以启动重塑。到目前为止，还没有研究发现 肌肉收缩诱导重塑事件的机制。代谢产物的快速时间尺度 积累和转运使这些分子成为理想的运动信号候选者。通过广泛 初步研究，我已经确定琥珀酸，三羧酸（TCA）循环中间体，是细胞外的 锻炼的信号。琥珀酸是G蛋白偶联受体琥珀酸受体1（SUCNR 1）的配体。 初步数据显示，SUCNR 1仅定位于骨骼肌中的非实质细胞。更 特别地，我鉴定了基质细胞作为SUCNR 1的高表达者。基质细胞是一种重要的 在重塑过程中起关键作用的人群。通过批量RNA测序分析，我观察到 琥珀酸-SUCNR 1信号依赖转录后急性运动干预在这个群体中。 具体来说，我看到了神经营养、ECM和细胞生长相关基因的SUCNR 1依赖性转录。 基于这些初步数据，我将测试肌肉细胞选择性释放琥珀酸的假设， 通过独特的质膜转运系统，通过直接激活局部 通过SUCNR 1信号传导的基质程序。使用分子和体内方法相结合，我的目标是 1）确定运动肌肉琥珀酸分泌的机制，2）确定运动肌肉琥珀酸分泌的生理机制， 运动后琥珀酸信号的重要性。这项拟议工作的结果将确定一个独特的 代谢物分泌机制和一种新的信号方式在运动肌肉。此外，拟议的 这项工作将提供对运动反应的分子基础的更深入的理解。

ABSTRACT Exercise is thought to be one of the most effective preventative measures for a variety of metabolic diseases including diabetes, obesity, and cardiovascular disease. However, the demands of exercise cause substantial mechanical and energetic stress on skeletal muscle. Muscles must undergo an extensive remodeling process in order to meet these demands. This process encompasses neurotrophic signaling, angiogenesis, extracellular matrix (ECM) remodeling, and hypertrophy. The remodeling process occurs rapidly following exercise and is dependent on the activity of a variety of non-parenchymal, resident cells. However, it is unknown how exercising skeletal muscle communicates with these cells to initiate remodeling. No study to date has identified the mechanism by which muscle contraction induces remodeling events. The rapid timescales of metabolite accumulation and transport render these molecules as ideal exercise-signaling candidates. Through extensive preliminary studies, I've identified succinate, a tricarboxylic acid (TCA) cycle intermediate, to be an extracellular signal of exercise. Succinate is a ligand for a g-protein coupled receptor, succinate receptor 1 (SUCNR1). Preliminary data shows that SUCNR1 is exclusively localized to non-parenchymal cells in skeletal muscle. More specifically, I identified stromal cells as high expressors of SUCNR1. Stromal cells are a prominent resident population that play a critical role in the remodeling process. Through bulk RNA-sequencing analysis, I observe succinate-SUCNR1 signaling dependent transcription following acute exercise intervention in this population. Specifically, I see a SUCNR1-dependent transcription of neurotrophic, ECM, and cell growth related genes. Building upon this preliminary data, I will test the hypothesis that muscle cells selectively release succinate, through a unique plasma membrane transport system, to mediate muscle remodeling by direct activation of local stromal programs through SUCNR1 signaling. Using a combination of molecular and in vivo approaches, I aim to 1) determine the mechanism of succinate secretion from exercising muscle and 2) determine the physiological importance of succinate signaling following exercise. The findings from this proposed work will identify a unique mechanism of metabolite secretion and a novel signaling modality in exercising muscle. Moreover, the proposed work will provide a deeper understanding of the molecular underpinnings of the exercise response.