The goal of this project is to develop an efficient system to evaluate dysferlin null pathology. Several approaches are being employed coordinately to determine which, if any, can reliably assess dyferlin dependent pathology based upon membrane leakage and/or transport changes. Downward running is known to place efferent stress on muscle fibers and may promote exacerbated pathology in dysferlin null mice. The large strain injury (LSI) model may also demonstrate reliable functional deficits in dysferlin mice. Evans blue dye (EBD) is being used in these paradigms to assess membrane damage and/or deficits in repair mechanisms. Additionally, a secreted form of alkaline phosphatase is being used to examine potential deficits in secretion in dysferlin null mice by assaying blood alkaline phosphatase levels. Comparative rescue studies will be performed with full length and minidysferlin using the most reliable assay developed in the optimization phase of this study.