Journal article
Defective membrane repair in dysferlin-deficient muscular dystrophy
Nature (London), Vol.423(6936), pp.168-172
2003
DOI: 10.1038/nature01573
PMID: 12736685
Abstract
Muscular dystrophy includes a diverse group of inherited muscle diseases characterized by wasting and weakness of skeletal muscle1. Mutations in dysferlin are linked to two clinically distinct muscle diseases, limb-girdle muscular dystrophy type 2B and Miyoshi myopathy, but the mechanism that leads to muscle degeneration is unknown2,3. Dysferlin is a homologue of the Caenorhabditis elegans fer-1 gene, which mediates vesicle fusion to the plasma membrane in spermatids4. Here we show that dysferlin-null mice maintain a functional dystrophin–glycoprotein complex but nevertheless develop a progressive muscular dystrophy. In normal muscle, membrane patches enriched in dysferlin can be detected in response to sarcolemma injuries. In contrast, there are sub-sarcolemmal accumulations of vesicles in dysferlin-null muscle. Membrane repair assays with a two-photon laser-scanning microscope demonstrated that wild-type muscle fibres efficiently reseal their sarcolemma in the presence of Ca2+. Interestingly, dysferlin-deficient muscle fibres are defective in Ca2+-dependent sarcolemma resealing. Membrane repair is therefore an active process in skeletal muscle fibres, and dysferlin has an essential role in this process. Our findings show that disruption of the muscle membrane repair machinery is responsible for dysferlin-deficient muscle degeneration, and highlight the importance of this basic cellular mechanism of membrane resealing in human disease.
Details
- Title: Subtitle
- Defective membrane repair in dysferlin-deficient muscular dystrophy
- Creators
- Dimple BANSAL - Howard Hughes Medical Institute, Department of Physiology and Biophysics and Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, United StatesKatsuya MIYAKE - Department of Cellular Biology and Anatomy, The Medical College of Georgia, Augusta, Georgia 30912, United StatesSteven S VOGEL - Laboratory of Molecular Physiology, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20852, United StatesSeverine GROH - Howard Hughes Medical Institute, Department of Physiology and Biophysics and Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, United StatesChien-Chang CHEN - Howard Hughes Medical Institute, Department of Physiology and Biophysics and Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, United StatesRoger WILLIAMSON - Department of Obstetrics and Gynecology, University of Iowa College of Medicine, Iowa City, Iowa 52242, United StatesPaul L MCNEIL - Department of Cellular Biology and Anatomy, The Medical College of Georgia, Augusta, Georgia 30912, United StatesKevin P CAMPBELL - Howard Hughes Medical Institute, Department of Physiology and Biophysics and Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, United States
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.423(6936), pp.168-172
- Publisher
- Nature Publishing; London
- DOI
- 10.1038/nature01573
- PMID
- 12736685
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Language
- English
- Date published
- 2003
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Obstetrics and Gynecology
- Record Identifier
- 9984020707602771
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