# Contribution of hydrogen sulfide to Duchenne muscular dystrophy pathophysiology

> **NIH NIH F30** · UNIVERSITY OF MINNESOTA · 2024 · $46,478

## Abstract

PROJECT SUMMARY
Duchenne muscular dystrophy (DMD) is one of the most severe neuromuscular diseases, with a median life
expectancy of 22 years. DMD results from the absence of the protein dystrophin, reducing the ability of muscle
to respond to stresses imposed by force generation and resulting in significant contractile dysfunction. In human
patients with DMD, this manifests in progressive skeletal muscle weakness beginning around 3-5 years of age
and cardiomyopathy and respiratory insufficiency around age 25, leading to death. In the mdx mouse model of
DMD, the absence of dystrophin also results in rapid and robust deficits in contractility, particularly loss of force
with repetitive eccentric contractions (ECCs) in skeletal muscle. The mechanisms by which mdx mice undergo
ECC force loss, and those which result in broader contractile deficits of striated muscle, are poorly understood.
Preliminary data from the Ervasti lab implicates elevated reactive oxygen species (ROS) and subsequent
hyperoxidation of the thiol proteome in DMD pathophysiology. Moreover, supplementation with the
gasotransmitter hydrogen sulfide (H2S), which is reduced in mdx muscle, completely protects mdx extensor
digitorum longus (EDL) muscle from ECC force loss in vitro. The mechanisms by which H2S protects from ECC
force loss, and its contributions to contractility in general, are not well characterized in the context of dystrophin-
deficient muscular dystrophy. The studies I designed in my proposal will test the hypothesis that elevations in
H2S will increase the persulfidation of reactive thiol residues on cysteines of contractile proteins, thereby
preventing hyperoxidation and associated contractile dysfunction. The experiments proposed here will strive to
characterize the effect of chronic, systemic H2S supplementation on DMD pathophysiology in vivo (Aim 1) and
define the effects of low H2S levels on oxidative post-translational modifications in mdx contractile proteins (Aim
2). A more complete understanding of contractile dysfunction and protection from force loss in mdx muscle is
critical to generating more efficacious therapeutics.
In addition to the research proposal, the following documents include a comprehensive and rigorous set of
research and clinical training plans that will allow for the successful completion of my MD and PhD degrees and
will enhance my development into a productive physician-scientist, able to drive cutting-edge translational
research and clinical care for my patients.

## Key facts

- **NIH application ID:** 10997019
- **Project number:** 1F30HL176040-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Katherine Sage Fallon
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $46,478
- **Award type:** 1
- **Project period:** 2024-08-01 → 2027-05-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997019

## Citation

> US National Institutes of Health, RePORTER application 10997019, Contribution of hydrogen sulfide to Duchenne muscular dystrophy pathophysiology (1F30HL176040-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10997019. Licensed CC0.

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