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Cell biology

Patches for wounded muscle

The stresses and strains imposed on certain cells mean that their membranes require constant repair. Study of the damage that affects muscle membranes reveals a new component of the repair process.

Cell membranes in tissues such as skin, gut and muscle are routinely exposed to mechanical damage, which can produce holes in them. When that damage is not repaired, the consequences can be severe — often resulting in cell death — and may contribute to the development of the muscle degenerative diseases termed muscular dystrophies. From a combination of observations on human muscular dystrophy patients and experiments with mice, Bansal et al.1 (page 168 of this issue) now report that a protein called dysferlin is a component of the mechanism for resealing the holes, and thus healing the muscle membrane.

Membrane resealing is generally carried out by a mechanism that resembles the calcium-regulated release of vesicles from a cell (exocytosis). The repair pathway is initiated by an influx of calcium through a wound, resulting in an increase in calcium levels at the site of injury. This, in turn, triggers the accumulation of vesicles, which fuse with one another and then with the plasma membrane, within the injury. A 'patch' is thereby added across the wounded area, resealing the plasma membrane2. The entire process — which remains largely mysterious — takes between ten and thirty seconds.

Specific participants include members of the SNARE and SNAP family of proteins, which are associated with vesicle fusion in nerve transmission. Among them is a protein called synaptotagmin, which is thought to act as a calcium sensor through its possession of two C2 domains. This feature means that it can bind phospholipids — which are the main components of membranes — in a calcium-dependent manner. The protein investigated by Bansal et al., dysferlin, is found in the muscle plasma membrane (sarcolemma) and in cytoplasmic vesicles, and its participation in membrane repair is all the more thought-provoking given its association with muscle degeneration.

Mutations in dysferlin cause two conditions — limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). Both are muscular dystrophies, which are all characterized by skeletal-muscle wasting and weakness (see Box 1). Many of the genes implicated in this group of diseases encode proteins that make up the 'dystrophin–glycoprotein complex', which straddles the sarcolemma and crosslinks structural components inside the cell with the extracellular environment3. The complex stabilizes muscle fibres by acting as a shock absorber for the forces of contraction and relaxation to which they are continually subjected. Mutations in any component of the dystrophin–glycoprotein complex lead to a secondary loss of other components, and to the eventual breakdown of the sarcolemma.

Muscle fibres isolated from LGMD2B/ MM patients exhibit disruptions to the sarcolemma that are characterized by the appearance of clusters of vesicles beneath the damage4. Bansal and colleagues generated mice that don't produce dysferlin (dysferlin-null mice), and these animals developed symptoms of progressive muscular dystrophy similar to those seen in human patients. But neither the dysferlin-null mice nor the LGMD2B patients showed any evidence of malfunction of the dystrophin–glycoprotein complex, or any sign of sarcolemma instability. So, given that dysferlin and several other proteins implicated in muscular dystrophy are not components of the dystrophin–glycoprotein complex, it was reasonable to conclude that other mechanisms could generate some of the features of muscular dystrophies.

The amino-acid sequence of dysferlin is 28% identical to that of Fer-1 protein found in the nematode worm Caenorhabditis elegans. In C. elegans, Fer-1 is proposed to mediate vesicle fusion to the plasma membrane of one cell type5. It is part of a growing family of 'ferlins', which include myoferlin and otoferlin, and is characterized by having six C2 domains (although only the first of them confers a calcium-dependent, phospholipid-binding ability). One LGMD2B patient has been found to have a point mutation in this C2 domain, reducing the domain's phospholipid-binding ability6. Myoferlin7 is also a sarcolemma protein, and its activity is increased in mice — mdx mice — that lack dystrophin, while otoferlin8 is associated with vesicle fusion in the inner ear.

Given this background, Bansal et al. reasoned that dysferlin could well be involved in calcium-dependent membrane repair, and they set out to test this hypothesis. To do this, they exposed isolated muscle fibres from normal — wild-type — mice to laser-induced membrane damage. Vesicles that stained positive for dysferlin accumulated beneath the sites of injury. To see if these vesicles could participate in membrane repair, Bansal et al. isolated muscle fibres from wild-type, mdx and dysferlin-null mice, exposed them to laser-induced membrane damage, and then timed how quickly their sarcolemmas resealed themselves in the presence and absence of external calcium. In both wild-type and mdx mice, sarcolemmas were resealed within a minute of being damaged, but only when calcium was present. The membranes of muscle fibres in dysferlin-null mice failed to reseal in any circumstances, confirming the role of dysferlin in membrane repair. So the damage seen in muscular dystrophies can indeed arise from a mechanism that is not associated with the dystrophin–glycoprotein complex.

Another group has reported9 that vesicles containing dysferlin undergo exocytosis in 57% of muscle fibres examined from patients with defective dysferlin, suggesting that dysferlin-containing vesicles may be part of an intracellular transport pathway. If myoferlin or otoferlin (or both) are also present in these vesicles, it seems likely that other ferlin family members function in membrane repair. If so, defects in proteins other than dysferlin would be implicated in producing certain hallmarks of muscular dystrophy by preventing efficient wound-healing.

Interestingly, dysferlin has also been reported10,11 to associate with the calcium-dependent protease calpain 3 and the sarcolemma protein caveolin-3. This is significant because defects in both of these proteins cause a type of muscular dystrophy, although neither protein belongs to the signalling routes implicated in the membrane repair process discussed here. Instead, modulation of calpain activity contributes to muscular dystrophies by disrupting cell-regulatory mechanisms, whereas caveolin-3 organizes lipid and protein constituents in the plasma membrane as part of a vesicular transport mechanism. Evidently, there may be yet more pathways to be discovered that, when disrupted in some way, ultimately lead to sarcolemma fragility.Footnote 1


  1. 1.

    *In this article, the volume number given in reference 8 of the reference list should be 21, and not 4 as printed.


  1. 1

    Bansal, D. et al. Nature 423, 168–172 (2003).

  2. 2

    McNeil, P. L. & Terasaki, M. Nature Cell Biol. 3, E124–E129 (2001).

  3. 3

    Durbeej, M. & Campbell, K. P. Curr. Opin. Genet. Dev. 12, 349–361 (2002).

  4. 4

    Piccolo, F., Moore, S. A., Ford, G. C. & Campbell, K. P. Ann. Neurol. 48, 902–912 (2000).

  5. 5

    Bashir, R. et al. Nature Genet. 20, 37–42 (1998).

  6. 6

    Davis, D. B., Doherty, K. R., Delmonte, A. J. & MacNally, E. M. J. Biol. Chem. 277, 22883–22888 (2002).

  7. 7

    Davis, D. B., Delmonte, A. J., Ly, C. T. & McNally, E. M. Hum. Mol. Genet. 9, 217–226 (2000).

  8. 8

    Yasunaga, S. et al. Nature Genet. 21*, 363–369 (1999).

  9. 9

    Selcen, D., Stilling, G. & Engel, A. G. Neurology 56, 1472–1481 (2001).

  10. 10

    Anderson, L. V. B. et al. Neuromusc. Disord. 10, 553–559 (2000).

  11. 11

    Matsuda, C. et al. Hum. Mol. Genet. 10, 1761–1766 (2001).

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Correspondence to Juliet A. Ellis.

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