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Cardiomyocyte-produced miR-339-5p mediates pathology in Duchenne muscular dystrophy cardiomyopathy. Hum Mol Genet 2021 Nov 16;30(23):2347-2361

Date

07/17/2021

Pubmed ID

34270708

Pubmed Central ID

PMC8600005

DOI

10.1093/hmg/ddab199

Scopus ID

2-s2.0-85121129104   1 Citation

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease characterized by severe, progressive muscle wasting. Cardiomyopathy has emerged as a leading cause of death in patients with DMD. The mechanisms contributing to DMD cardiac disease remain under investigation and specific therapies available are lacking. Our prior work has shown that DMD-iPSC-derived cardiomyocytes (DMD-iCMs) are vulnerable to oxidative stress injury and chronic exposure to DMD-secreted exosomes impaired the cell's ability to protect against stress. In this study, we sought to examine a mechanism by which DMD cardiac exosomes impair cellular response through altering important stress-responsive genes in the recipient cells. Here, we report that DMD-iCMs secrete exosomes containing altered microRNA (miR) profiles in comparison to healthy controls. In particular, miR-339-5p was upregulated in DMD-iCMs, DMD exosomes and mdx mouse cardiac tissue. Restoring dystrophin in DMD-iCMs improved the cellular response to stress and was associated with downregulation of miR-339-5p, suggesting that it is disease-specific. Knockdown of miR-339-5p was associated with increased expression of MDM2, GSK3A and MAP2K3, which are genes involved in important stress-responsive signaling pathways. Finally, knockdown of miR-339-5p led to mitochondrial protection and a reduction in cell death in DMD-iCMs, indicating miR-339-5p is involved in direct modulation of stress-responsiveness. Together, these findings identify a potential mechanism by which exosomal miR-339-5p may be modulating cell signaling pathways that are important for robust stress responses. Additionally, these exosomal miRs may provide important disease-specific targets for future therapeutic advancements for the management and diagnosis of DMD cardiomyopathy.

Author List

Gartz M, Beatka M, Prom MJ, Strande JL, Lawlor MW

Authors

Melanie Gartz PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Biomarkers
Cardiomyopathies
Disease Susceptibility
Dystrophin
Exosomes
Gene Expression Regulation
Gene Knockdown Techniques
Humans
MicroRNAs
Muscle, Skeletal
Muscular Dystrophy, Duchenne
Myocytes, Cardiac
Stress, Physiological