The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics & Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases & School of Medical Technology & Department of Cell Biology, Tianjin Medical University, Guangdong Road, Tianjin, 300203, China.
Medical Genetic Institute of Henan Province, Henan Provincial Key laboratory of Genetic Diseases and Functional Genomics, National Health Commission Key Laboratory of Birth Defects Prevention, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450000, China.
Cell Death Differ. 2022 Oct;29(10):1928-1940. doi: 10.1038/s41418-022-00979-0. Epub 2022 Mar 19.
Cardiomyopathy is a primary cause of mortality in Duchenne muscular dystrophy (DMD) patients. Mechanistic understanding of cardiac fibrosis holds the key to effective DMD cardiomyopathy treatments. Here we demonstrate that upregulation of Wilms' tumor 1 (Wt1) gene in epicardial cells increased cardiac fibrosis and impaired cardiac function in 8-month old mdx mice lacking the RNA component of telomerase (mdx/mTR). Levels of phosphorylated IƙBα and p65 significantly rose in mdx/mTR dystrophic hearts and Wt1 expression declined in the epicardium of mdx/mTR mice when nuclear factor κB (NF-κB) and inflammation were inhibited by metformin. This demonstrates that Wt1 expression in epicardial cells is dependent on inflammation-triggered NF-κB activation. Metformin effectively prevented cardiac fibrosis and improved cardiac function in mdx/mTR mice. Our study demonstrates that upregulation of Wt1 in epicardial cells contributes to fibrosis in dystrophic hearts and metformin-mediated inhibition of NF-κB can ameliorate the pathology, and thus showing clinical potential for dystrophic cardiomyopathy. Translational Perspective: Cardiomyopathy is a major cause of mortality in Duchenne muscular dystrophy (DMD) patients. Promising exon-skipping treatments are moving to the clinic, but getting sufficient dystrophin expression in the heart has proven challenging. The present study shows that Wilms' Tumor 1 (Wt1) upregulation in epicardial cells is primarily responsible for cardiac fibrosis and dysfunction of dystrophic mice and likely of DMD patients. Metformin effectively prevents cardiac fibrosis and improves cardiac function in dystrophic mice, thus representing a treatment option for DMD patients on top of existing therapies.
心肌病是杜氏肌营养不良症（DMD）患者死亡的主要原因。对心肌纤维化的机制理解是有效治疗 DMD 心肌病的关键。在这里，我们证明了在缺乏端粒酶 RNA 成分的 mdx 小鼠（mdx/mTR）中，心外膜细胞中 Wilms 肿瘤 1（Wt1）基因的上调增加了心肌纤维化并损害了心脏功能。mdx/mTR 营养不良心脏中磷酸化 IκBα 和 p65 的水平显着升高，并且当核因子 κB（NF-κB）和炎症被二甲双胍抑制时，Wt1 在 mdx/mTR 小鼠的心外膜中的表达下降。这表明心外膜细胞中 Wt1 的表达依赖于炎症触发的 NF-κB 激活。二甲双胍可有效预防 mdx/mTR 小鼠的心肌纤维化并改善心脏功能。我们的研究表明，心外膜细胞中 Wt1 的上调导致营养不良心脏中的纤维化，并且二甲双胍介导的 NF-κB 抑制可以改善病理学，从而为营养不良性心肌病显示出临床潜力。翻译角度：心肌病是杜氏肌营养不良症（DMD）患者死亡的主要原因。有前途的外显子跳跃治疗正在进入临床，但在心脏中获得足够的肌营养不良蛋白表达已被证明具有挑战性。本研究表明，心外膜细胞中 Wilms 肿瘤 1（Wt1）的上调是导致心肌纤维化和营养不良小鼠心功能障碍的主要原因，并且可能是 DMD 患者的主要原因。二甲双胍可有效预防营养不良小鼠的心肌纤维化并改善心脏功能，因此除了现有的治疗方法外，还为 DMD 患者提供了一种治疗选择。
