# Endothelial Reactive Oxygen Species in Exercise Metabolism

> **NIH NIH R56** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2024 · $354,200

## 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 consists of multiple cell types, such as myocytes, vascular
endothelial cells, pericytes, and immune cells. When subjected to exercise stress, these cells communicate with
one another to coordinate the heightened energy production required by the skeletal muscle. 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 molecules known for their ability to both initiate signaling cascades and to
cause damage. Skeletal muscle produces ROS in response to exercise, but whether ROS harm or protect the
muscle has been debated. Initially, ROS were believed to be solely deleterious, contributing to conditions like
diabetes and sarcopenia. However, recent findings indicate that ROS play a crucial role in skeletal muscle's
metabolic adaptation to exercise. Despite this, we still have limited knowledge about where ROS are produced,
the enzymes involved, and the specific processes that rely on ROS for beneficial signaling during exercise.
Building on our previous research, our current proposal focuses on NADPH oxidase 4 (NOX4), a ROS-producing
enzyme we identified as a critical factor in initiating skeletal muscle's metabolic responses to exercise.
Importantly, 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 reduced metabolic response to acute exercise.
Based on these findings, we will investigate the hypothesis that endothelial signaling, dependent on NOX4,
plays a crucial role in determining the mitochondrial metabolic responses to exercise in skeletal muscle.
To investigate this, we will utilize advanced tools that allow us to specifically manipulate the expression of Nox4
in endothelial cells. This will enable us to gain new insights into exercise-induced endothelial signaling and
examine the impact of endothelial cell-derived ROS on both 1) endothelial signaling and 2) the mitochondrial
responses to exercise in skeletal muscle. Ultimately, we hope these findings will contribute to developing
targeted exercise interventions and potentially provide a foundation for treatment strategies based on exercise
as medicine.

## Key facts

- **NIH application ID:** 11175783
- **Project number:** 1R56AR083948-01
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** SIOBHAN M CRAIGE
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $354,200
- **Award type:** 1
- **Project period:** 2024-09-20 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11175783

## Citation

> US National Institutes of Health, RePORTER application 11175783, Endothelial Reactive Oxygen Species in Exercise Metabolism (1R56AR083948-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11175783. Licensed CC0.

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