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Defective membrane repair in dysferlin-deficient muscular dystrophy

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.

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Figure 1: Complete loss of dysferlin expression in dysferlin-null mice.
Figure 2: Dysferlin-null mice develop progressive muscular dystrophy.
Figure 3: Normal expression of DGC components and a structurally stable sarcolemma in dysferlin-null mice.
Figure 4: Vesicle accumulation and dysferlin-enriched membrane patches on the damaged muscle fibres.
Figure 5: Defective resealing of membranes in dysferlin-null muscle.

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References

  1. Cohn, R. D. & Campbell, K. P. Molecular basis of muscular dystrophies. Muscle Nerve 23, 1456–1471 (2000)

    Article  CAS  Google Scholar 

  2. Bashir, R. et al. A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nature Genet. 20, 37–42 (1998)

    Article  CAS  Google Scholar 

  3. Liu, J. et al. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nature Genet. 20, 31–36 (1998)

    Article  CAS  Google Scholar 

  4. Achanzar, W. E. & Ward, S. A nematode gene required for sperm vesicle fusion. J. Cell Sci. 110, 1073–1081 (1997)

    CAS  PubMed  Google Scholar 

  5. Piccolo, F., Moore, S. A., Ford, G. C. & Campbell, K. P. Intracellular accumulation and reduced sarcolemmal expression of dysferlin in limb-girdle muscular dystrophies. Ann. Neurol. 48, 902–912 (2000)

    Article  CAS  Google Scholar 

  6. Matsuda, C. et al. The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle. Hum. Mol. Genet. 10, 1761–1766 (2001)

    Article  CAS  Google Scholar 

  7. Anderson, L. V. et al. Secondary reduction in calpain 3 expression in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy (primary dysferlinopathies). Neuromusc. Disord. 10, 553–559 (2000)

    Article  CAS  Google Scholar 

  8. Straub, V., Rafael, J. A., Chamberlain, J. S. & Campbell, K. P. Animal models for muscular dystrophy show different patterns of sarcolemmal disruption. J. Cell Biol. 139, 375–385 (1997)

    Article  CAS  Google Scholar 

  9. Duclos, F. et al. Progressive muscular dystrophy in α-sarcoglycan-deficient mice. J. Cell Biol. 142, 1461–1471 (1998)

    Article  CAS  Google Scholar 

  10. Durbeej, M. & Campbell, K. P. Muscular dystrophies involving the dystrophin–glycoprotein complex: an overview of current mouse models. Curr. Opin. Genet. Dev. 12, 349–361 (2002)

    Article  CAS  Google Scholar 

  11. Ervasti, J. M., Ohlendieck, K., Kahl, S. D., Gaver, M. G. & Campbell, K. P. Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle. Nature 345, 315–319 (1990)

    Article  ADS  CAS  Google Scholar 

  12. Petrof, B. J., Shrager, J. B., Stedman, H. H., Kelly, A. M. & Sweeney, H. L. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc. Natl Acad. Sci. USA 90, 3710–3714 (1993)

    Article  ADS  CAS  Google Scholar 

  13. Clarke, M. S., Khakee, R. & McNeil, P. L. Loss of cytoplasmic basic fibroblast growth factor from physiologically wounded myofibers of normal and dystrophic muscle. J. Cell Sci. 106, 121–133 (1993)

    CAS  PubMed  Google Scholar 

  14. Coral-Vazquez, R. et al. Disruption of the sarcoglycan–sarcospan complex in vascular smooth muscle: a novel mechanism for cardiomyopathy and muscular dystrophy. Cell 98, 465–474 (1999)

    Article  CAS  Google Scholar 

  15. McNeil, P. L. & Khakee, R. Disruptions of muscle fiber plasma membranes. Role in exercise-induced damage. Am. J. Pathol. 140, 1097–1109 (1992)

    CAS  PubMed  PubMed Central  Google Scholar 

  16. McNeil, P. L. & Terasaki, M. Coping with the inevitable: how cells repair a torn surface membrane. Nature Cell Biol. 3, E124–E129 (2001)

    Article  CAS  Google Scholar 

  17. Bi, G. Q., Alderton, J. M. & Steinhardt, R. A. Calcium-regulated exocytosis is required for cell membrane resealing. J. Cell Biol. 131, 1747–1758 (1995)

    Article  CAS  Google Scholar 

  18. Miyake, K. & McNeil, P. L. Vesicle accumulation and exocytosis at sites of plasma membrane disruption. J. Cell Biol. 131, 1737–1745 (1995)

    Article  CAS  Google Scholar 

  19. Steinhardt, R. A., Bi, G. & Alderton, J. M. Cell membrane resealing by a vesicular mechanism similar to neurotransmitter release. Science 263, 390–393 (1994)

    Article  ADS  CAS  Google Scholar 

  20. Reddy, A., Caler, E. V. & Andrews, N. W. Plasma membrane repair is mediated by Ca2+-regulated exocytosis of lysosomes. Cell 106, 157–169 (2001)

    Article  CAS  Google Scholar 

  21. Davis, D. B., Doherty, K. R., Delmonte, A. J. & McNally, E. M. Calcium-sensitive phospholipid binding properties of normal and mutant ferlin C2 domains. J. Biol. Chem. 277, 22883–22888 (2002)

    Article  CAS  Google Scholar 

  22. McNeil, P. L., Vogel, S. S., Miyake, K. & Terasaki, M. Patching plasma membrane disruptions with cytoplasmic membrane. J. Cell Sci. 113, 1891–1902 (2000)

    CAS  PubMed  Google Scholar 

  23. McNeil, P. L., Miyake, K. & Vogel, S. S. The self-sealing membrane concept. Proc. Natl Acad. Sci. USA 100, 4592–4597 (2003)

    Article  ADS  CAS  Google Scholar 

  24. Ohlendieck, K. & Campbell, K. P. Dystrophin-associated proteins are greatly reduced in skeletal muscle from mdx mice. J. Cell Biol. 115, 1685–1694 (1991)

    Article  CAS  Google Scholar 

  25. Durbeej, M. et al. Disruption of the β-sarcoglycan gene reveals pathogenetic complexity of limb-girdle muscular dystrophy type 2E. Mol. Cell 5, 141–151 (2000)

    Article  CAS  Google Scholar 

  26. Anderson, L. V. et al. Dysferlin is a plasma membrane protein and is expressed early in human development. Hum. Mol. Genet. 8, 855–861 (1999)

    Article  CAS  Google Scholar 

  27. Miner, J. H. et al. The laminin alpha chains: expression, developmental transitions, and chromosomal locations of α1-5, identification of heterotrimeric laminins 8–11, and cloning of a novel α3 isoform. J. Cell Biol. 137, 685–701 (1997)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all members of the Campbell laboratory for the critical reading of this manuscript, discussions and supplying critical reagents; and M. Hassebrock, S. Lowen, E. Hurst and K. Garringer for technical assistance. D. Bansal was supported by American Heart Predoctoral Fellowship (Heartland). We thank the University of Iowa DNA Core Facility, which is supported in part by the Diabetes Endocrinology Research Center and the University of Iowa Roy J. and Lucille A. Carver College of Medicine. We also thank University of Iowa Central Microscopy Research Facility and the Medical College of Georgia Imaging Core. This work was supported by the Muscular Dystrophy Association (K.P.C.). P.L.McN. is supported by NASA, and S.S.V. by NIH. K.P.C. is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Kevin P. Campbell.

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Bansal, D., Miyake, K., Vogel, S. et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423, 168–172 (2003). https://doi.org/10.1038/nature01573

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