Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Dis Model Mech. 2020 Nov 13;13(11):dmm045559. doi: 10.1242/dmm.045559.
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 and 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.
心肌病是杜兴肌营养不良症（DMD）患者早期死亡的主要原因。需要更好地了解分子发病机制，以开发有效的治疗方法。外泌体（exo）是分泌的囊泡，通过其 RNA、脂质和蛋白质货物发挥作用。外泌体在疾病发病机制中的作用尚不清楚。来源于干细胞的外泌体已在 DMD 小鼠心脏中显示出心脏保护作用。然而，尚不清楚供体细胞类型的疾病状态如何影响外泌体的功能。在这里，我们试图确定 DMD 心肌细胞（DMD-iCMs）在长期暴露于 DMD 心脏外泌体（DMD-exo）后的表型反应。DMD-iCMs 容易受到应激，表现为活性氧的产生、线粒体膜电位和细胞死亡水平。长期暴露于未受影响的外泌体（N-exo）是有保护作用的。相比之下，长期暴露于 DMD-exo 没有保护作用，并且应激反应通过抑制 DMD-exo 的分泌得到改善，而外泌体表面肽而不是 microRNA（miR）货物参与了 DMD-exo 的病理作用。外泌体表面分析显示 N-exo 肽与 PI3K-Akt 信号通路有关。转录组谱分析确定了与暴露于 N-或 DMD-exo 相关的独特变化。此外，DMD-exo miR 货物调节了伤害性途径，包括 p53 和 TGF-β。这些发现揭示了健康和疾病状态之间外泌体货物的变化，导致不良后果。在这里，DMD-exo 包含了 miR 变化，这些变化促进了 DMD-iCMs 对应激的易感性。识别外泌体货物中的这些分子变化和有效的表型可能为杜兴肌营养不良症心肌病的发病机制提供新的线索。本文有一篇与论文第一作者的第一人称访谈。
