Inflammation in a severe model of dystrophic cardiomyopathy contains a high proportion of T-cells that contribute to onset of pathology

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder characterized by progressive muscle degeneration and cardiomyopathy leading to heart failure. While the inflammatory environment in dystrophic skeletal muscle has been well-studied, little is known about inflammation in the progression of DMD cardiomyopathy due to the lack of adequate animal models. To address this, we developed the Fiona/dko mouse model, which exhibits severe, isolated dystrophic cardiomyopathy. In this study, we used Fiona/dko mice to characterize the immune cell composition in dystrophic heart and investigated the contribution of T-cells to the onset and progression of cardiac pathology. Flow cytometry analysis revealed that T-cells constitute a significant proportion of the immune cell population in Fiona/dko hearts, in contrast to the predominantly myeloid signature observed in dystrophic skeletal muscle. Furthermore, we demonstrated that T-cell infiltration precedes the development of cardiac fibrosis and dysfunction in Fiona/dko mice and that depletion of circulating CD3+ T-cells ameliorates early pathology, suggesting a role for T-cells in the initiation and persistence of dystrophic cardiomyopathy. These findings highlight the distinct inflammatory environment in the dystrophic heart and provide new insights into the pathogenesis of DMD cardiomyopathy, paving the way for the development of targeted anti-inflammatory therapies. Overall design: To investigate gene expression differences between more severe cardiomyopathy in Fiona/dko mice compared to less severe Het/Fiona mice, 9-month-old mice of each genotype, including males and females for each, were dissected and RNA was extracted from heart ventricles to send for bulk RNA sequencing.

杜氏肌营养不良症（Duchenne muscular dystrophy, DMD）是一种以进行性肌肉变性及引发心力衰竭的心肌病为特征的重症神经肌肉疾病。尽管目前对营养不良性骨骼肌的炎症微环境已有较为充分的研究，但由于缺乏合适的动物模型，学界对杜氏肌营养不良症心肌病进展过程中的炎症反应仍知之甚少。为解决这一研究空白，本研究构建了Fiona/dko小鼠模型，该模型可表现出严重的孤立性营养不良性心肌病。本研究利用Fiona/dko小鼠对营养不良性心脏的免疫细胞组成进行了表征，并探究了T细胞（T cells）在心脏病理发生与进展中的作用。流式细胞术分析结果显示，Fiona/dko小鼠心脏的免疫细胞群中T细胞占比显著，这与营养不良性骨骼肌中以髓系细胞为主要特征的免疫谱形成鲜明对比。此外，本研究证实，在Fiona/dko小鼠中，T细胞浸润早于心脏纤维化与心功能障碍的发生；且清除循环中的CD3+ T细胞可改善早期病理状态，这提示T细胞在营养不良性心肌病的起始与持续进展中发挥作用。上述研究结果凸显了营养不良性心脏中独特的炎症微环境，为阐明杜氏肌营养不良症心肌病的发病机制提供了新视角，也为靶向抗炎疗法的开发铺平了道路。实验整体设计：为探究Fiona/dko小鼠的重症心肌病与病情较轻的Het/Fiona小鼠之间的基因表达差异，本研究选取各基因型的9月龄小鼠（雌雄各半）进行解剖，从心室中提取RNA并送至实验室开展批量RNA测序（bulk RNA sequencing）。