Mechanisms of Force Loss in Injured and Dystrophic Skeletal Muscle

描述(申请人提供)：来自几个小组的积累证据支持这样的概念，即MDX小鼠(Duchenne肌营养不良症小鼠模型)肌肉力量的减少和对损伤的敏感性增加与大量畸形肌纤维的存在有关，而畸形的肌纤维本身更容易产生力量的减少和损伤。在老年MDX肌肉中，畸形肌纤维的出现也显著增加，这可能是MDX肌肉损伤易感性随年龄增加的潜在原因。我们将通过两个具体目标在营养不良和受损的骨骼肌中验证这一假说：1)比较营养不良骨骼肌的几种模型中形态改变的肌纤维的患病率、结构和功能特性，以及2)将细胞变化(例如形态、组织病理学等)与肌肉损伤后发生的更多临床变化(例如力量丧失和医学成像)联系起来。在这两个目标中，我们将把在细胞水平上看到的变化与使用非侵入性MRI成像看到的变化联系起来。这一关键比较的结果将是重要的，因为我们正在寻求更准确和可靠的非侵入性措施来跟踪儿童营养不良过程的时间进展，以及治疗急性肌肉损伤的新疗法。

DESCRIPTION (provided by applicant): Accumulating evidence from several groups supports the concept that the decreased force and increased susceptibility to damage in muscles of mdx mice (mouse model for Duchenne muscular dystrophy) correlates with the presence of a significant number of malformed myofibers, which themselves generate decreased force and damage more readily. The occurrence of malformed myofibers also increases dramatically in aged mdx muscles, potentially accounting for the age-dependent increase in the susceptibility to muscle damage in the mdx. We will test this hypothesis in dystrophic and injured skeletal muscle through 2 specific aims: 1) to compare the prevalence, structure, and functional properties of myofibers with altered morphology in several models of dystrophic skeletal muscle, and 2) to link the cellular changes (e.g. morphology, histopathology, etc) to the more clinical changes (e.g. force loss and medical imaging) that occur after muscle injury. Throughout both aims, we will relate the changes seen at the cellular level to changes seen using non-invasive MRI imaging. Results of this critical comparison will be important as we seek more precise and reliable non-invasive measures to follow the temporal progression of the dystrophic process in children, and novel therapies to treat acute muscle injury.