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Defective membrane repair in dysferlin-deficient muscular dystrophy

Author

Listed:
  • Dimple Bansal

    (University of Iowa Roy J. and Lucille A. Carver College of Medicine)

  • Katsuya Miyake

    (The Medical College of Georgia)

  • Steven S. Vogel

    (National Institutes of Health)

  • Séverine Groh

    (University of Iowa Roy J. and Lucille A. Carver College of Medicine)

  • Chien-Chang Chen

    (University of Iowa Roy J. and Lucille A. Carver College of Medicine)

  • Roger Williamson

    (University of Iowa College of Medicine)

  • Paul L. McNeil

    (The Medical College of Georgia)

  • Kevin P. Campbell

    (University of Iowa Roy J. and Lucille A. Carver College of Medicine)

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.

Suggested Citation

  • Dimple Bansal & Katsuya Miyake & Steven S. Vogel & Séverine Groh & Chien-Chang Chen & Roger Williamson & Paul L. McNeil & Kevin P. Campbell, 2003. "Defective membrane repair in dysferlin-deficient muscular dystrophy," Nature, Nature, vol. 423(6936), pages 168-172, May.
  • Handle: RePEc:nat:nature:v:423:y:2003:i:6936:d:10.1038_nature01573
    DOI: 10.1038/nature01573
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    Cited by:

    1. Hsiang-Ling Huang & Giovanna Grandinetti & Sarah M. Heissler & Krishna Chinthalapudi, 2024. "Cryo-EM structures of the membrane repair protein dysferlin," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Mahtab Tavasoli & Sarah Lahire & Stanislav Sokolenko & Robyn Novorolsky & Sarah Anne Reid & Abir Lefsay & Meredith O. C. Otley & Kitipong Uaesoontrachoon & Joyce Rowsell & Sadish Srinivassane & Molly , 2022. "Mechanism of action and therapeutic route for a muscular dystrophy caused by a genetic defect in lipid metabolism," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Viviane Tran & Sarah Nahlé & Amélie Robert & Inès Desanlis & Ryan Killoran & Sophie Ehresmann & Marie-Pier Thibault & David Barford & Kodi S. Ravichandran & Martin Sauvageau & Matthew J. Smith & Marie, 2022. "Biasing the conformation of ELMO2 reveals that myoblast fusion can be exploited to improve muscle regeneration," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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