Altered exosomal microRNA (miR) expression may modulate the expression of stress response genes and contribute to cardiac disease in Duchenne muscular dystrophy (DMD), according to a new study published in the journal Human Molecular Genetics. More precisely, the study showed that exosomal miR-339-5p was upregulated in DMD-induced pluripotent stem cell-derived cardiomyocytes and the cardiac tissue of a mouse model of DMD.
“These exosomal miRs may provide important disease-specific targets for future therapeutic advancements for the management and diagnosis of DMD cardiomyopathy,” wrote first authors Melanie Gartz, PhD, MS, MHS, and the co-authors of the study.
In their previous research, the authors had shown that DMD heart cells are vulnerable to oxidative stress injury and that chronic exposure to DMD exosomes impairs cells’ ability to protect themselves from stress.
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In order to better understand the effect of cardiac exosomes on cellular response to stress in DMD, the team conducted a series of experiments using DMD-induced pluripotent stem cell-derived cardiomyocytes and mdx mice, the most widely used animal model for DMD research.
They found that DMD-induced pluripotent stem cell-derived cardiomyocytes secrete exosomes containing altered miR profiles compared to healthy controls. In particular, miR-339-5p was upregulated. This was also the case in the heart tissue of mdx mice.
When they restored dystrophin expression, the researchers found that miR-339-5p expression was downregulated and cellular response to stress was improved. (Dystrophin is the protein that is missing in DMD). The team concluded that miR-339-5p was disease-specific.
The researchers found that directly knocking down the expression of miR-339-5p in DMD-induced pluripotent stem cell-derived cardiomyocytes also led to mitochondrial protection and a reduction in cell death. The knockdown was associated with a higher expression of genes coding for proteins such as MDM2, GSK3A, and MAP2K3, which play important roles in stress-responsive signaling pathways.
“Together, these findings identify a potential mechanism by which exosomal miR-339-5p may be modulating cell signaling pathways which are important for robust stress responses,” the researchers concluded.
Cardiomyopathy is a leading cause of death in patients with DMD but the mechanisms leading to cardiomyopathy are not well understood and specific treatments are lacking.
Gartz M, Beatka M, Prom MJ, Strande JL, Lawlor MW. Cardiomyocyte-produced miR-339-5p mediates pathology in Duchenne muscular dystrophy cardiomyopathy. Hum Mol Genet. 2021; ddab199. doi:10.1093/hmg/ddab199