Correcting the DMD gene in cardiomyocytes differentiated from Duchenne muscular dystrophy (DMD) patient cells using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 restores the levels of reactive oxygen species (ROS) and improves the survival of the cells, according to a new study published in Stem Cell Reports. Moreover, reducing ROS levels with N-acetyl-L-cysteine (NAC), ataluren (PTC124), or idebenone also improves the survival of these cells.

Therefore, the authors of the study proposed that targeting ROS production may be a promising strategy to treat cardiomyopathy in patients with DMD. Cardiomyopathy is a major cause of death in this population of patients. 

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To better understand cardiomyopathic features in DMD, a team of researchers led by Maurilio Sampaolesi, PhD, from the Translational Cardiomyology Lab, Stem Cell and Developmental Biology, Department of Development and Regeneration at the Catholic University of Leuven, Belgium, differentiated cardiomyocytes from DMD patient-specific human induced pluripotent stem cells in culture.

They found that these cardiomyocytes had enhanced premature cell death because of significantly high levels of intracellular ROS. This elevation in ROS was caused by depolarized mitochondria and increased levels of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4).

The researchers showed that stimulating adenosine triphosphate (ATP) production using idebenone counteracted oxidative stress in these cells. This is because ATP binds to NOX4 and inhibits the production of ROS at least partially, the researchers explained.

They concluded that interfering with any of the early cellular events leading to the excessive production of ROS could improve mitochondrial activity and the contractile function of cardiomyocytes.

DMD is caused by a mutation in the DMD gene, which encodes for the dystrophin protein that is essential for the health of muscle cells, including cardiomyocytes. The lack of dystrophin in DMD dysregulates many pathways in the heart, including calcium homeostasis, and leads to oxidative stress, inflammation, and functional ischemia.

Reference

Duelen R, Costamagna D, Gilbert G, et al. Human iPSC model reveals a central role for NOX4 and oxidative stress in Duchenne cardiomyopathy. Stem Cell Reports. Published online January 27, 2022. doi:10.1016/j.stemcr.2021.12.019