# Endothelial Signaling in Exercise Metabolism

> **NIH NIH R03** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2024 · $72,753

## Abstract

PROJECT SUMMARY
Exercise is a powerful strategy to improve skeletal muscle metabolism that can both prevent and reverse
disease. However, the complex signaling that drives the immediate and long-term changes in muscle metabolism
is incompletely understood. Skeletal muscle is composed of numerous cell types (e.g., myocytes, vascular
endothelial cells, pericytes, immune cells, etc.). In response to exercise stress, these cells "talk" to each other to
orchestrate the increased energy production needed by the skeletal muscle. Understanding the signaling initiated
and the pathways activated with cell type clarity will provide the molecular resolution necessary to unravel the
protective effects of exercise. Our long-term goal is to understand intercellular skeletal muscle signaling initiated
in response to exercise, thus informing strategies to promote health and prevent disease.
Reactive oxygen species (ROS) are fast-acting, transient molecules recognized for their ability to initiate
signaling cascades. The current proposal builds upon our K01 research, where we have identified a ROSproducer,
NADPH oxidase 4 (NOX4), as a critical initiator of skeletal muscle metabolic responses to exercise.
lmportanUy, this enzyme is most highly expressed in the vascular endothelial cells of skeletal muscle. If we
remove this enzyme from only the endothelium, we observe a blunted metabolic response to acute exercise. We
have previously shown that endothelial NOX4 increases expression and activity of endothelial nitric oxide
synthase (eNOS). Based on these observations, the current proposal seeks to understand if eNOS lies
downstream of NOX4 in mediating skeletal muscle responses to exercise. Therefore, we propose to uncover the
role of eNOS in skeletal muscle mitochondrial metabolism and determine whether eNOS and nitric oxide
production activate exercise-induced mitophagy. We will utilize innovative tools to address these questions and
expect this project to reveal novel information regarding exercise-endothelial signaling. These studies will
generate new hypotheses and will advance the Craige Lab research program by uncovering the underlying
pathways influenced by eNOS. Ultimately, we hope these findings will contribute to the development of targeted
exercise interventions and potentially even provide a foundation for treatment strategies based on exercise as
medicine.

## Key facts

- **NIH application ID:** 10793119
- **Project number:** 1R03AR083493-01
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** SIOBHAN M CRAIGE
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $72,753
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10793119

## Citation

> US National Institutes of Health, RePORTER application 10793119, Endothelial Signaling in Exercise Metabolism (1R03AR083493-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10793119. Licensed CC0.

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