Mechanisms of Force Loss in Injured and Dystrophic Skeletal Muscle

描述（由申请人提供）：从几个小组积累的证据支持mdx小鼠（杜氏肌营养不良小鼠模型）肌肉力量下降和对损伤易感性增加的概念，与大量畸形肌纤维的存在相关，而畸形肌纤维本身更容易产生力量下降和损伤。在老年mdx肌肉中，畸形肌纤维的发生也显著增加，这可能解释了mdx肌肉损伤易感性的年龄依赖性增加。我们将在营养不良和受伤的骨骼肌中通过两个特定目的来验证这一假设：1)比较几种营养不良骨骼肌模型中形态学改变的肌纤维的患病率、结构和功能特性；2)将细胞变化（如形态学、组织病理学等）与肌肉损伤后发生的更多临床变化（如力损失和医学成像）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。当我们寻求更精确、可靠的非侵入性方法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时，这一关键比较的结果将是重要的。

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. PUBLIC HEALTH RELEVANCE: We know a great deal about diagnosing muscle injuries and the genetic basis of muscular dystrophies, but the pathophysiology is less clear. Fibers with abnormal morphology have been identified in diseased, regenerating, and exercised muscle, yet their frequency and functional significance remain unclear. The impact of our findings will be of value in monitoring muscular dystrophy disease progression in animal models and could be useful in following the course of chronic muscle diseases in humans. There is keen interest in identifying specific pathological processes in order to develop rationale therapies, but also to use biological markers and outcome measures that can monitor the response to therapies.