The Role of Cytokeratins in Skeletal Muscle Injury

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The goal of this research is to increase understanding of the mechanisms underlying muscle injury, treatment, and recovery. My hypothesis is that cytokeretins K8 & K19 play an integral part in the organization and function of the sarcolemma of skeletal muscle. I will use functional, morphological, and molecular biological approaches to test this hypothesis through 3 specific aims: 1) a: To adapt a model of muscle injury to mice and compare subsequent contractile function to mice with a known dystrophinopathy (mdx mice), b: to compare forces of mdx and wild-type (wt) single-fibers to the whole-muscle findings and to mdx fibers transfected with a virus expressing a functional dystrophin, 2) To determine whether muscles lacking cytokeratin K8 or K19 are dystrophic and/or more susceptible to injury, and if replacement of the missing subunit into muscle fibers by adenoviral transfection corrects the dystrophy or alters susceptibility to injury, 3) To learn if overexpression of K8 or K19 results in myopathy. There are marked similarities in the histopathology of some muscular dystrophies and the changes in muscle induced by injury. The proposed research is designed to elucidate some of the shared cellular and molecular mechanisms.