# NADPH Oxidase and Autophagic Dysfunction in Duchenne Muscular Dystrophy

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $338,239

## Abstract

Project Summary
Duchenne muscular dystrophy (DMD) is a devastating type of muscular dystrophy, with an incidence of 1 in
every 3500 males. DMD is an X-linked, muscle-wasting disease caused by mutations in the cytoskeletal
protein dystrophin. Young DMD patients experience muscle damage that is followed by regeneration; however,
as the disease progresses regeneration is impeded and muscle fibers are progressively replaced by
connective tissue and fatty deposits. Profound muscle weakness results in decreased mobility by 10 to 12
year of age and eventually death by the age of 20 to 30 due to respiratory and/or cardiac failure. While there is
currently no treatment for the disease, many different therapeutic approaches for DMD are entering clinical
trials. Accumulating evidence supports the idea that the elevated susceptibility to damage in mdx muscles
correlates with the presence of increased sarcolemmal Ca2+ influx and increased production of reactive oxygen
species (ROS). Impaired autophagy, a cellular process to clear damaged constituents, has recently been
implicated in the disease process. Ongoing work by our group has found that increased ROS generation from
Nox2 contributes to altered redox balance and Ca2+ homeostasis in skeletal muscle from the mouse model of
muscular dystrophy (Mdx). We have recently shown that Src, a non-receptor tyrosine kinase, acts as a redox
switch to activate Nox2. Genetic inhibition of Nox2 decreases the exuberant ROS generation, decreases Src
kinase activity, and rescues the defective autophagy in skeletal muscle from Mdx mice. Furthermore, we have
shown that inhibiting Src kinase in-vitro decreases oxidative stress and improves autophagy. In preliminary
data we have recently found that treating Mdx mice with the Src kinase inhibitor dasatinib improves autophagic
flux and skeletal muscle function. The overall goal of this proposal is to test whether inhibition of Src kinase
can prevent oxidative stress, impaired autophagic flux, and muscle pathology in Mdx mice. If successful, the
proposed research will provide a novel therapeutic target, Src kinase, for DMD. Given that Src kinase
inhibitors are in clinical development for the treatment of cancer, results from these studies will be valuable for
future clinical trials for the treatment of DMD.

## Key facts

- **NIH application ID:** 10226262
- **Project number:** 5R01AR061370-10
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** George G Rodney
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $338,239
- **Award type:** 5
- **Project period:** 2012-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226262

## Citation

> US National Institutes of Health, RePORTER application 10226262, NADPH Oxidase and Autophagic Dysfunction in Duchenne Muscular Dystrophy (5R01AR061370-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10226262. Licensed CC0.

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