Journal article
Gene transfer establishes primacy of striated vs. smooth muscle sarcoglycan complex in limb-girdle muscular dystrophy
Proceedings of the National Academy of Sciences - PNAS, Vol.100(15), pp.8910-8915
07/22/2003
DOI: 10.1073/pnas.1537554100
PMCID: PMC166412
PMID: 12851463
Abstract
Limb-girdle muscular dystrophy types 2E and F are characterized by skeletal
muscle weakness and often cardiomyopathy and are due to mutations in the genes
encoding β- and δ-sarcoglycan. We previously demonstrated that loss
of sarcoglycans in smooth muscle leads to constrictions of the
microvasculature that contributes to the cardiac phenotype. It is unclear how
vasculature abnormalities affect skeletal muscle. We injected recombinant
β- or δ-sarcoglycan adenoviruses into skeletal muscles of
corresponding null mice. We hypothesized that the adenoviruses would not
transduce vascular smooth muscle, and we would only target skeletal muscle.
Indeed, sustained expression of intact sarcoglycan–sarcospan complex was
noted at the sarcolemma, neuromuscular junction, myotendinous junction, and in
peripheral nerve, but not in vascular smooth muscle. Gene transfer of the
corresponding deleted sarcoglycan gene preserved sarcolemmal integrity,
prevented pathological dystrophy and hypertrophy, and protected against
exercised-induced damage. We conclude that vascular dysfunction is not a
primary cause of β- and δ-sarcoglycan-deficient muscular dystrophy.
In addition, we show successful functional rescue of entire muscles after
adenovirus-mediated gene delivery. Thus, virus-mediated gene transfer of
sarcoglycans to skeletal muscle in combination with pharmacological prevention
of cardiomyopathy constitute promising therapeutic strategies for limb-girdle
muscular dystrophies.
Details
- Title: Subtitle
- Gene transfer establishes primacy of striated vs. smooth muscle sarcoglycan complex in limb-girdle muscular dystrophy
- Creators
- Madeleine Durbeej - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242-1101; andShanna M Sawatzki - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242-1101; andRita Barresi - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242-1101; andKathleen M Schmainda - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242-1101; andValérie Allamand - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242-1101; andDaniel E Michele - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242-1101; andKevin P Campbell - Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242-1101; and
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.100(15), pp.8910-8915
- DOI
- 10.1073/pnas.1537554100
- PMID
- 12851463
- PMCID
- PMC166412
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Language
- English
- Date published
- 07/22/2003
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984020732702771
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