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.

骨骼肌是适合运动但慢性疾病的最塑料人体器官之一。慢性退化/炎症性肌肉疾病与进行性无力和固定性有关。尽管特定的信号通路可能会指示每个单个疾病机制，但组织和细胞结构的慢性重塑是主要原则。然而，尚未详细介绍组织纤维化，但是，骨骼肌肉纤维细胞结构结构的细胞详细变化尚未详细解决。我们认为，慢性肌肉疾病中至少有一半是通过细胞重塑（例如纤维分支或精神错乱的晶格几何形状。 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).尤其是在使用定量亚细胞形态计量学之前，从未研究过后一种模型，后者能够揭示对人类退化蛋白聚集的结构改变的见解。为此，我们将使用从小鼠到老鼠的单个纤维进行详细的与年龄有关的研究，并使它们接受我们的先进成像技术和结构分析。作为一个特殊目标，我们还将将光学形态计量学与同一细胞中等距产生的记录相结合，以为我们的目标提供校准，以便在肌肉纤维和组织中使用SHG成像作为通过光学手段来预测力损失和虚弱的手段。该项目不仅将有助于我们对进行性肌肉无力的分子和生物物理起源的理解，而且还为肌肉研究界提供了一种新颖的强大成像工具。