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

点击翻译按钮获取中文摘要

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.