Novak James S, Lischin Amy, Uapinyoying Prech, Hindupur Ravi, Moon Young Jae, Bhattacharya Surajit, Tiufekchiev Sarah, Barone Victoria, Mázala Davi A G, Gamu Iteoluwakishi H, Walters Gabriela, Jaiswal Jyoti K
Center for Genetic Medicine Research, Children's National Research Institute, Children's National Research and Innovation Campus, Children's National Hospital, Washington, D.C., 20012, USA.
Departments of Pediatrics and Genomics and Precision Medicine, The George Washington University School of Medicine and Health Sciences, Washington, D.C., 20037, USA.
bioRxiv. 2025 Jan 29:2024.08.15.607998. doi: 10.1101/2024.08.15.607998.
Absence of dystrophin protein causes cardiac dysfunction in patients with Duchenne muscular dystrophy (DMD). Unlike boys with DMD, the common mouse model of DMD (B10-) does not manifest cardiac deficits until late adulthood. This has limited our understanding of the mechanism and therapeutic approaches to target the pediatric onset of cardiac pathology in DMD. Here we show that the mouse model on the DBA/2J genetic background (D2-) displays juvenile-onset cardiac degeneration. Molecular and histological analysis revealed that cardiac damage in this model is linked to increased leukocyte chemotactic signaling and an inability to resolve inflammation. These deficiencies result in chronic inflammation and fibrotic conversion of the extracellular matrix (ECM) in the juvenile D2-mdx heart. To address these pathologies, we tested the utility of pro-resolution therapy to clear chronic cardiac inflammation. Use of an N-formyl peptide receptor (FPR) agonist helped physiologically resolve inflammation and mitigate the downstream events that lead to fibrotic degeneration of cardiomyocytes, preventing juvenile onset cardiac muscle loss. These results establish the utility of D2- model to study events associated with pediatric-onset cardiac damage and demonstrates pro-resolution therapy as an alternate to anti-inflammatory therapy for treating cardiac degenerative pathology responsible for cardiomyopathy in DMD patients.
肌营养不良蛋白的缺失会导致杜氏肌营养不良症（DMD）患者出现心脏功能障碍。与患有DMD的男孩不同，常见的DMD小鼠模型（B10-）直到成年后期才会出现心脏缺陷。这限制了我们对DMD儿童期心脏病变发病机制和治疗方法的理解。在此我们表明，DBA/2J遗传背景的小鼠模型（D2-）表现出幼年性心脏变性。分子和组织学分析显示，该模型中的心脏损伤与白细胞趋化信号增加以及炎症无法消退有关。这些缺陷导致幼年D2-mdx心脏出现慢性炎症和细胞外基质（ECM）的纤维化转化。为了解决这些病理问题，我们测试了促消退疗法清除慢性心脏炎症的效用。使用N-甲酰肽受体（FPR）激动剂有助于从生理上消退炎症，并减轻导致心肌细胞纤维化变性的下游事件，防止幼年性心肌损失。这些结果确立了D2-模型在研究与儿童期心脏损伤相关事件方面的效用，并证明促消退疗法可作为抗炎疗法的替代方法，用于治疗导致DMD患者心肌病的心脏退行性病变。
