Dowling Paul, Gargan Stephen, Zweyer Margit, Sabir Hemmen, Henry Michael, Meleady Paula, Swandulla Dieter, Ohlendieck Kay
Department of Biology, Maynooth University, National University of Ireland, Maynooth, Co. Kildare, Ireland; Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare.
Department of Neonatology and Paediatric Intensive Care, Children's Hospital, University of Bonn, Bonn.
Eur J Transl Myol. 2021 Mar 26;31(1):9627. doi: 10.4081/ejtm.2021.9627.
The neuromuscular disorder Duchenne muscular dystrophy is a multi-systemic disease that is caused by a primary abnormality in the X-chromosomal Dmd gene. Although progressive skeletal muscle wasting and cardio-respiratory complications are the most serious symptoms that are directly linked to the almost complete loss of the membrane cytoskeletal protein dystrophin, dystrophic patients also suffer from gastrointestinal dysfunction. In order to determine whether proteome-wide changes potentially occur in the gastrointestinal system due to dystrophin deficiency, total tissue extracts from the interface between the stomach wall and the pancreas of the mdx-4cv model of dystrophinopathy were analysed by mass spectrometry. Following the proteomic establishment of both smooth muscle markers of the gastrointestinal system and key enzymes of the pancreas, core members of the dystrophin-glycoprotein complex, including dystrophin, dystroglycans, sarcoglycans, dystrobrevins and syntrophins were identified in this tissue preparation. Comparative proteomics revealed a drastic reduction in dystrophin, sarcoglycan, dystroglycan, laminin, titin and filamin suggesting loss of cytoskeletal integrity in mdx-4cv smooth muscles. A concomitant increase in various mitochondrial enzymes is indicative of metabolic disturbances. These findings agree with abnormal gastrointestinal function in dystrophinopathy.
神经肌肉疾病杜氏肌营养不良症是一种多系统疾病，由X染色体上的Dmd基因原发性异常引起。尽管进行性骨骼肌萎缩和心肺并发症是与膜细胞骨架蛋白抗肌萎缩蛋白几乎完全缺失直接相关的最严重症状，但营养不良患者也存在胃肠功能障碍。为了确定由于抗肌萎缩蛋白缺乏，胃肠道系统是否可能发生全蛋白质组变化，通过质谱分析了抗肌萎缩蛋白病mdx-4cv模型胃壁与胰腺之间界面的总组织提取物。在通过蛋白质组学确定了胃肠道系统的平滑肌标志物和胰腺的关键酶之后，在该组织制剂中鉴定出了抗肌萎缩蛋白-糖蛋白复合物的核心成员，包括抗肌萎缩蛋白、抗肌萎缩蛋白聚糖、肌聚糖、肌萎缩蛋白短肽和肌营养不良蛋白结合蛋白。比较蛋白质组学显示，mdx-4cv平滑肌中抗肌萎缩蛋白、肌聚糖、抗肌萎缩蛋白聚糖、层粘连蛋白、肌联蛋白和细丝蛋白急剧减少，表明细胞骨架完整性丧失。各种线粒体酶的同时增加表明存在代谢紊乱。这些发现与抗肌萎缩蛋白病中异常的胃肠功能一致。
