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Duchenne muscular dystrophy (DMD) cardiomyocyte-secreted exosomes promote the pathogenesis of DMD-associated cardiomyopathy. Dis Model Mech 2020 Nov 13;13(11)

Date

11/15/2020

Pubmed ID

33188007

Pubmed Central ID

PMC7673361

DOI

10.1242/dmm.045559

Scopus ID

2-s2.0-85096154674   9 Citations

Abstract

Cardiomyopathy is a leading cause of early mortality in Duchenne muscular dystrophy (DMD). There is a need to gain a better understanding of the molecular pathogenesis for the development effective therapies. Exosomes (exo) are secreted vesicles and exert effects via their RNA, lipid and protein cargo. The role of exosomes in disease pathology is unknown. Exosomes derived from stem cells have demonstrated cardioprotection in the murine DMD heart. However, it is unknown how the disease status of the donor cell type influences exosome function. Here, we sought to determine the phenotypic responses of DMD cardiomyocytes (DMD-iCMs) after long-term exposure to DMD cardiac exosomes (DMD-exo). DMD-iCMs were vulnerable to stress, evidenced by production of reactive oxygen species, the mitochondrial membrane potential and cell death levels. Long-term exposure to non-affected exosomes (N-exo) was protective. By contrast, long-term exposure to DMD-exo was not protective, and the response to stress improved with inhibition of DMD-exo secretion in vitro and in vivo The microRNA (miR) cargo, but not exosome surface peptides, was implicated in the pathological effects of DMD-exo. Exosomal surface profiling revealed N-exo peptides associated with PI3K-Akt signaling. Transcriptomic profiling identified unique changes with exposure to either N- or DMD-exo. Furthermore, DMD-exo miR cargo regulated injurious pathways, including p53 and TGF-beta. The findings reveal changes in exosomal cargo between healthy and diseased states, resulting in adverse outcomes. Here, DMD-exo contained miR changes, which promoted the vulnerability of DMD-iCMs to stress. Identification of these molecular changes in exosome cargo and effectual phenotypes might shed new light on processes underlying DMD cardiomyopathy.This article has an associated First Person interview with the first author of the paper.

Author List

Gartz M, Lin CW, Sussman MA, Lawlor MW, Strande JL

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
Chien-Wei Lin PhD Assistant Professor in the Institute for Health and Equity department at Medical College of Wisconsin




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

Animals
Cardiomyopathies
Cardiotonic Agents
Cell Death
Cell Line
Exosomes
Female
Humans
Mice, Inbred C57BL
MicroRNAs
Muscular Dystrophy, Duchenne
Myocytes, Cardiac
Paracrine Communication
Proteome
Stress, Physiological
Transcription, Genetic