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

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2022 · $34,515

## Abstract

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.

## Key facts

- **NIH application ID:** 10370313
- **Project number:** 5F31DK128924-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Anita Reddy
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $34,515
- **Award type:** 5
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370313

## Citation

> US National Institutes of Health, RePORTER application 10370313, Examining the role of succinate-SUCNR1 signaling in skeletal muscle remodeling following exercise. (5F31DK128924-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10370313. Licensed CC0.

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