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rAAV6-microdystrophin rescues aberrant Golgi complex organization in mdx skeletal muscles
Justin M Percival1, Paul Gregorevic, Guy L Odom
1Department of Physiology and Biophysics, University of Washington, Box 357290, 1959 NE Pacific Street, Seattle, WA 98195, USA. 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 DeltaR4-R23/DeltaCT 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.
Insights
Golgi complex distribution is abnormal in Duchenne muscular dystrophy mouse models. Micro-dystrophin expression restored Golgi organization, revealing a new therapeutic target for muscular dystrophy.
Area of Science:
- Cell Biology
- Neuroscience
- Genetics
Background:
- Muscular dystrophies encompass severe degenerative muscle diseases.
- Mutations in Golgi-resident glycosyltransferases link Golgi complex function to muscle disease.
- The Golgi complex's role in sarcolemmal stability is a recent area of research.
Purpose of the Study:
- To investigate Golgi complex organization in dystrophin-deficient muscles of mdx mice.
- To determine if abnormal Golgi distribution contributes to muscular dystrophy pathology.
- To explore the therapeutic potential of micro-dystrophin in restoring Golgi function.
Main Methods:
- Examined Golgi complex organization in skeletal muscles of mdx mice.
- Assessed Golgi localization during muscle necrosis and regeneration phases.
- Investigated the role of the microtubule cytoskeleton in Golgi mislocalization.
- Utilized recombinant adeno-associated virus 6-mediated micro-dystrophin expression.
Main Results:
- Aberrant organization, mislocalization, and improper concentration of the Golgi complex were observed in mdx mouse skeletal muscles.
- Golgi complex localization was disrupted post-necrosis and impaired during regeneration in mdx muscle fibers.
- Microtubule cytoskeleton disruption partially explained aberrant Golgi localization.
- Micro-dystrophin expression restored Golgi complex distribution and improved microtubule organization.
Conclusions:
- Abnormal Golgi complex distribution is a novel pathological feature in mdx mouse skeletal muscle.
- Micro-dystrophin expression effectively rescues Golgi distribution abnormalities.
- This suggests a new functional role for micro-dystrophin in maintaining Golgi complex organization.
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