Mechanisms of Force Loss in Injured and Dystrophic Skeletal Muscle

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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.