Defective membrane repair in dysferlin-deficient muscular dystrophy

Dimple Bansal, Katsuya Miyake, Steven S. Vogel, Séverine Groh, Chien Chang Chen, Roger Williamson, Paul L McNeil, Kevin P. Campbell

Research output: Contribution to journalArticle

615 Citations (Scopus)

Abstract

Muscular dystrophy includes a diverse group of inherited muscle diseases characterized by wasting and weakness of skeletal muscle. 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 unknown. Dysferlin is a homologue of the Caenorhabditis elegans fer-I gene, which mediates vesicle fusion to the plasma membrane in spermatids. 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.

Original languageEnglish (US)
Pages (from-to)168-172
Number of pages5
JournalNature
Volume423
Issue number6936
DOIs
StatePublished - May 8 2003

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Muscular Dystrophies
Muscles
Membranes
Sarcolemma
Wasting Syndrome
Dystrophin
Spermatids
Skeletal Muscle Fibers
Caenorhabditis elegans
Photons
Glycoproteins
Skeletal Muscle
Lasers
Cell Membrane
Mutation
Wounds and Injuries

ASJC Scopus subject areas

  • General

Cite this

Bansal, D., Miyake, K., Vogel, S. S., Groh, S., Chen, C. C., Williamson, R., ... Campbell, K. P. (2003). Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature, 423(6936), 168-172. https://doi.org/10.1038/nature01573

Defective membrane repair in dysferlin-deficient muscular dystrophy. / Bansal, Dimple; Miyake, Katsuya; Vogel, Steven S.; Groh, Séverine; Chen, Chien Chang; Williamson, Roger; McNeil, Paul L; Campbell, Kevin P.

In: Nature, Vol. 423, No. 6936, 08.05.2003, p. 168-172.

Research output: Contribution to journalArticle

Bansal, D, Miyake, K, Vogel, SS, Groh, S, Chen, CC, Williamson, R, McNeil, PL & Campbell, KP 2003, 'Defective membrane repair in dysferlin-deficient muscular dystrophy', Nature, vol. 423, no. 6936, pp. 168-172. https://doi.org/10.1038/nature01573
Bansal D, Miyake K, Vogel SS, Groh S, Chen CC, Williamson R et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature. 2003 May 8;423(6936):168-172. https://doi.org/10.1038/nature01573
Bansal, Dimple ; Miyake, Katsuya ; Vogel, Steven S. ; Groh, Séverine ; Chen, Chien Chang ; Williamson, Roger ; McNeil, Paul L ; Campbell, Kevin P. / Defective membrane repair in dysferlin-deficient muscular dystrophy. In: Nature. 2003 ; Vol. 423, No. 6936. pp. 168-172.
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