Progressive Muscle Dysfunction resulting from chronic Remodeling of Cellular Architecture in inherited Muscle Diseases- Advanced Second Harmonic Generation Microcopy and quantitative Morphometry in skeletal Muscles from Animal Models of Duchenne Muscular

遗传性肌肉疾病中细胞结构慢性重塑导致的进行性肌肉功能障碍 - 杜兴肌肉动物模型骨骼肌的先进二次谐波发生显微镜和定量形态测量

• 批准号: 241798291
• 负责人: Professor Dr. Oliver Friedrich
• 金额: --
• 依托单位: Lehrstuhl für Medizinische Biotechnologie (MBT)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/241798291?language=en
• 关键词: Progressive; Muscle; Dysfunction; resulting; chronic

Skeletal muscle is one of the most plastic human organs adapting to exercise but also to chronic disease. Chronic degenerative/inflammatory muscle diseases are associated with progressive weakness and immobility. Although specific signaling pathways may fingerprint each individual disease mechanism, chronic remodeling of tissue and cell architecture is the main common principle. Tissue fibrosis is well understood, however, cellular detailed changes in skeletal muscle fibre cytoarchitecture have not been addressed in detail. We believe that at least half of the weakness in chronic muscle disorders is accounted for by cellular remodeling, e.g. fibre branching or deranged myofibrillar lattice geometry. In this project, we aim to apply state-of-the art multiphoton Second Harmonic Generation (SHG) microscopy in two animal models of inherited degenerative disease: mdx mice lacking dystrophin (model for Duchenne muscular dystrophy, DMD) and desmin-null and mutated desmin-knock-in mice (model for desminopathy). Especially the latter model has never been studied before using quantitative subcellular morphometry that is capable of revealing insights into structural alterations in degenerative protein aggregation myofibrillar myopathies in humans. For this, we will perform a detailed age-related study using single fibres from young to old mice and subject them to our advanced imaging technology and structure analysis. As a special goal, we will also combine optical morphometry with recordings of isometric force production in the same cells to provide a calibration for our goal to use SHG imaging in muscle fibres and tissue as a means to predict force loss and weakness by optical means. The project will not only contribute to our understanding of molecular and biophysical origins of progressive muscle weakness but also provide a novel powerful imaging tool to the muscle research community.

骨骼肌是适应运动和慢性疾病的最具可塑性的人体器官之一。慢性退行性/炎症性肌肉疾病与进行性虚弱和不动有关。虽然特定的信号传导途径可以识别每个个体的疾病机制，但组织和细胞结构的慢性重塑是主要的共同原则。组织纤维化是很好的理解，然而，骨骼肌纤维细胞结构的细胞详细的变化还没有得到详细解决。我们认为，慢性肌肉疾病中至少有一半的虚弱是由细胞重塑引起的，例如纤维分支或紊乱的肌原纤维晶格几何形状。在这个项目中，我们的目标是在两种遗传性退行性疾病的动物模型中应用最先进的多光子二次谐波发生（SHG）显微镜：缺乏肌营养不良蛋白的mdx小鼠（Duchenne肌营养不良症，DMD模型）和结蛋白缺失和突变的结蛋白敲入小鼠（结蛋白病模型）。特别是后者的模型从来没有被研究之前，使用定量亚细胞形态学，能够揭示在人类退行性蛋白质聚集肌原纤维肌病的结构改变的见解。为此，我们将使用从年轻到年老的小鼠的单纤维进行详细的年龄相关研究，并将其置于我们先进的成像技术和结构分析中。作为一个特殊的目标，我们还将联合收割机光学形态测量 在相同的细胞中等长力产生的记录，以提供我们的目标，使用SHG成像在肌肉纤维和组织作为一种手段，通过光学手段预测力的损失和弱点的校准。该项目不仅有助于 不仅有助于我们理解进行性肌无力的分子和生物物理起源，而且还提供了一种新的强大的成像工具， 给肌肉研究界。