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

摘要 运动被认为是预防各种代谢性疾病最有效的措施之一。 包括糖尿病、肥胖症和心血管疾病。然而，锻炼的需求导致了相当大的 骨骼肌的机械和能量压力。肌肉必须经历广泛的重塑过程 以满足这些需求。这一过程包括神经营养信号、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，并且 依赖于各种非实质、常驻细胞的活动。然而，目前还不清楚如何锻炼 骨骼肌与这些细胞沟通，启动重塑。到目前为止，还没有研究确定 肌肉收缩引发重塑事件的机制。代谢物的快速时标 积累和运输使这些分子成为理想的运动信号候选者。通过广泛的 初步研究，我已经确定琥珀酸，一种三羧酸(TCA)循环中间体，是一种胞外物质 这是锻炼的信号。琥珀酸是一种G蛋白偶联受体琥珀酸受体1(SUCNR1)的配体。 初步数据显示，SUCNR1仅定位于骨骼肌中的非实质细胞。更多 具体地说，我发现基质细胞是SUCNR1的高表达细胞。基质细胞是一种重要的生物 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 在这一人群中，急性运动干预后的琥珀酸-SUCNR1信号依赖转录。 具体地说，我看到了神经营养、细胞外基质和细胞生长相关基因的依赖于SUCNR1的转录。 在这个初步数据的基础上，我将测试肌肉细胞选择性地释放琥珀酸的假设， 通过独特的质膜运输系统，通过直接激活局部 间质通过SUCNR1信号进行编程。使用分子和体内方法的组合，我的目标是 为了1)确定运动肌肉分泌琥珀酸的机制和2)确定生理的 运动后传递琥珀酸信号的重要性。这项拟议工作的发现将确定一种独特的 运动肌肉中代谢物分泌的机制和一种新的信号方式。此外，建议的 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.