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Updated: Oct 5, 2025
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Published on: May 5, 2020
Human iPSC model reveals a central role for NOX4 and oxidative stress in Duchenne cardiomyopathy
Robin Duelen1, Domiziana Costamagna2, Guillaume Gilbert3
1Translational Cardiomyology Lab, Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, Herestraat 49 - O&N4 - bus 804, 3000 Leuven, Belgium.
Insights
Duchenne muscular dystrophy (DMD) cardiomyopathy involves increased cell death from oxidative stress. Targeting reactive oxygen species (ROS) production and NADPH oxidase 4 (NOX4) shows promise for improving survival in DMD patient-derived cells.
Area of Science:
- Stem cell biology
- Cardiovascular research
- Genetics and molecular biology
Background:
- Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration.
- Cardiomyopathy is a leading cause of premature mortality in DMD patients.
- Understanding the cellular mechanisms of DMD cardiomyopathy is crucial for developing effective therapies.
Purpose of the Study:
- To model Duchenne muscular dystrophy (DMD) cardiomyopathy using patient-specific induced pluripotent stem cells (hiPSCs).
- To investigate the role of oxidative stress and mitochondrial dysfunction in DMD-affected cardiomyocytes (CMs).
- To identify potential therapeutic targets for mitigating DMD cardiomyopathy.
Main Methods:
- Generation and differentiation of hiPSCs from DMD patients into cardiomyocytes (CMs).
- Assessment of cell death, reactive oxygen species (ROS) levels, mitochondrial function, and NADPH oxidase 4 (NOX4) expression.
- Utilized CRISPR-Cas9 gene editing to correct the Dystrophin gene.
- Tested the efficacy of ROS-reducing agents (N-acetyl-L-cysteine, ataluren, idebenone) and adenosine triphosphate (ATP) stimulation.
Main Results:
- DMD hiPSC-derived CMs exhibited increased premature cell death linked to elevated ROS, mitochondrial depolarization, and higher NOX4 levels.
- CRISPR-Cas9 correction of Dystrophin normalized ROS levels.
- Treatment with NAC, ataluren, and idebenone, as well as ATP stimulation, enhanced hiPSC-CM survival.
- Adenosine triphosphate (ATP) was found to partially inhibit ROS production by binding to NOX4.
Conclusions:
- Oxidative stress and NOX4 activity are key contributors to cell death in DMD cardiomyopathy.
- Targeting ROS production and NOX4 represents a promising therapeutic strategy for DMD cardiomyopathy.
- Modulating ATP levels may offer a novel approach to counteract oxidative stress in DMD.
Abstract:
Duchenne muscular dystrophy (DMD) is a progressive muscle disorder caused by mutations in the Dystrophin gene. Cardiomyopathy is a major cause of early death. We used DMD-patient-specific human induced pluripotent stem cells (hiPSCs) to model cardiomyopathic features and unravel novel pathologic insights. Cardiomyocytes (CMs) differentiated from DMD hiPSCs showed enhanced premature cell death due to significantly elevated intracellular reactive oxygen species (ROS) resulting from depolarized mitochondria and increased NADPH oxidase 4 (NOX4). CRISPR-Cas9 correction of Dystrophin restored normal ROS levels. ROS reduction by N-acetyl-L-cysteine (NAC), ataluren (PTC124), and idebenone improved hiPSC-CM survival. We show that oxidative stress in DMD hiPSC-CMs was counteracted by stimulating adenosine triphosphate (ATP) production. ATP can bind to NOX4 and partially inhibit the ROS production. Considering the complexity and the early cellular stress responses in DMD cardiomyopathy, we propose targeting ROS production and preventing detrimental effects of NOX4 on DMD CMs as promising therapeutic strategy.
