Gargan Stephen, Dowling Paul, Zweyer Margit, Henry Michael, Meleady Paula, Swandulla Dieter, Ohlendieck Kay
Department of Biology, Maynooth University, National University of Ireland, W23 F2H6 Maynooth, Ireland.
Kathleen Lonsdale Institute for Human Health Research, Maynooth University, W23 F2H6 Maynooth, Ireland.
Life (Basel). 2022 Oct 22;12(11):1679. doi: 10.3390/life12111679.
Deficiency in the membrane cytoskeletal protein dystrophin is the underlying cause of the progressive muscle wasting disease named Duchenne muscular dystrophy. In order to detect novel disease marker candidates and confirm the complexity of the pathobiochemical signature of dystrophinopathy, mass spectrometric screening approaches represent ideal tools for comprehensive biomarker discovery studies. In this report, we describe the comparative proteomic analysis of young versus aged diaphragm muscles from wild type versus the dystrophic mouse model of X-linked muscular dystrophy. The survey confirmed the drastic reduction of the dystrophin-glycoprotein complex in the diaphragm muscle and concomitant age-dependent changes in key markers of muscular dystrophy, including proteins involved in cytoskeletal organization, metabolite transportation, the cellular stress response and excitation-contraction coupling. Importantly, proteomic markers of the regulation of membrane repair, tissue regeneration and reactive myofibrosis were detected by mass spectrometry and changes in key proteins were confirmed by immunoblotting. Potential disease marker candidates include various isoforms of annexin, the matricellular protein periostin and a large number of collagens. Alterations in these proteoforms can be useful to evaluate adaptive, compensatory and pathobiochemical changes in the intracellular cytoskeleton, myofiber membrane integrity and the extracellular matrix in dystrophin-deficient skeletal muscle tissues.
膜细胞骨架蛋白肌营养不良蛋白的缺乏是名为杜兴氏肌营养不良症的进行性肌肉萎缩疾病的根本原因。为了检测新的疾病标志物候选物并确认肌营养不良症病理生化特征的复杂性，质谱筛选方法是全面生物标志物发现研究的理想工具。在本报告中，我们描述了来自野生型与X连锁肌营养不良症的营养不良小鼠模型的年轻与老年膈肌肌肉的比较蛋白质组学分析。该研究证实了膈肌中肌营养不良蛋白-糖蛋白复合物的急剧减少以及肌肉营养不良关键标志物的年龄依赖性变化，包括参与细胞骨架组织、代谢物运输、细胞应激反应和兴奋-收缩偶联的蛋白质。重要的是，通过质谱检测到膜修复、组织再生和反应性肌纤维化调节的蛋白质组学标志物，并通过免疫印迹证实了关键蛋白质的变化。潜在的疾病标志物候选物包括膜联蛋白的各种异构体、基质细胞蛋白骨膜蛋白和大量胶原蛋白。这些蛋白质形式的改变有助于评估肌营养不良蛋白缺乏的骨骼肌组织中细胞内细胞骨架、肌纤维膜完整性和细胞外基质的适应性、代偿性和病理生化变化。
