rAAV6-Microdystrophin Rescues Aberrant Golgi Complex Organization in mdx Skeletal Muscles

Authors

  • Justin M. Percival,

    Corresponding author
    1. Department of Physiology and Biophysics, University of Washington, Box 357290, 1959 NE Pacific Street, Seattle, WA 98195, USA
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  • Paul Gregorevic,

    1. Department of Neurology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
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  • Guy L. Odom,

    1. Department of Neurology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
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  • Glen B. Banks,

    1. Department of Neurology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
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  • Jeffrey S. Chamberlain,

    1. Department of Neurology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
    2. Department of Biochemistry, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
    3. The Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
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  • Stanley C. Froehner

    1. Department of Physiology and Biophysics, University of Washington, Box 357290, 1959 NE Pacific Street, Seattle, WA 98195, USA
    2. The Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
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Justin M. Percival, justinp2@u.washington.edu

Abstract

Muscular dystrophies are a diverse group of severe degenerative muscle diseases. Recent interest in the role of the Golgi complex (GC) in muscle disease has been piqued by findings that several dystrophies result from mutations in putative Golgi-resident glycosyltransferases. Given this new role of the Golgi in sarcolemmal stability, we hypothesized that abnormal Golgi distribution, regulation and/or function may constitute part of the pathology of other dystrophies, where the primary defect is independent of Golgi function. Thus, we investigated GC organization in the dystrophin-deficient muscles of mdx mice, a mouse model for Duchenne muscular dystrophy. We report aberrant organization of the synaptic and extrasynaptic GC in skeletal muscles of mdx mice. The GC is mislocalized and improperly concentrated at the surface and core of mdx myofibers. Golgi complex localization is disrupted after the onset of necrosis and normal redistribution is impaired during regeneration of mdx muscle fibers. Disruption of the microtubule cytoskeleton may account in part for aberrant GC localization in mdx myofibers. Golgi complex distribution is restored to wild type and microtubule cytoskeleton organization is significantly improved by recombinant adeno-associated virus 6-mediated expression of ΔR4-R23/ΔCT microdystrophin showing a novel mode of microdystrophin functionality. In summary, GC distribution abnormalities are a novel component of mdx skeletal muscle pathology rescued by microdystrophin expression.

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