Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Molecular mechanisms of muscular dystrophies: old and new players

Key Points

  • Muscular dystrophies (MDs) are diseases that predominantly affect the skeletal muscle. They are characterized by increasing muscle weakness and a typical histological appearance of progressive muscle-fibre damage and accumulation of connective and fatty tissue. Over 30 different genes that are expressed in a wide variety of muscle-fibre organelles have now been associated with MDs.

  • Dystrophin, along with members of the dystrophin-associated protein complex (DAPC), link the intracellular cytoskeleton with the extracellular matrix and protect the muscle cell from damage caused by the force created during muscle contraction. Dystrophin was the first gene shown to cause MD when mutated, and many of the DAPC proteins have subsequently been shown to cause MDs, or their expression or localization is affected in these diseases.

  • An increasing number of genes have been identified that, when mutated, lead to inappropriate glycosylation of α-dystroglycan, which is a component of the DAPC. As this glycosylation is essential for the interaction of α-dystroglycan with its protein binding partners, incorrect processing disturbs these connections, rendering the muscle fibre more susceptible to damage and therefore the dystrophic process occurs.

  • Fragile nuclei can also lead to MD, as illustrated by the effects of mutant emerin, lamin A and lamin C, which are proteins that are localized at the nuclear membrane. Expression studies have found that the MDs that are caused by mutations of the emerin and LMNA genes involve the retinoblastoma protein (Rb1) and MyoD transcriptional regulatory pathway.

  • The sarcomere is situated within the sarcoplasm of the muscle cell and is the site of muscle contraction. Although not traditionally associated with MDs, mutant proteins of the sarcomere have now been identified as causing these muscle diseases.

Abstract

The study of the muscle cell in the muscular dystrophies (MDs) has shown that mutant proteins result in perturbations of many cellular components. MDs have been associated with mutations in structural proteins, signalling molecules and enzymes as well as mutations that result in aberrant processing of mRNA or alterations in post-translational modifications of proteins. These findings have not only revealed important insights for cell biologists, but have also provided unexpected and exciting new approaches for therapy.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Microscopic images of cross-sections of human skeletal muscle.
Figure 2: Dystrophin binds to the DAPC at the sarcolemma.
Figure 3: A cross-section of a myofibre showing the approximate position of important component proteins.

Similar content being viewed by others

References

  1. Hackman, P. et al. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am. J. Hum. Genet. 71, 492–500 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Muchir, A. et al. Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum. Mol. Genet. 9, 1453–1459 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Bonne, G. et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery–Dreifuss muscular dystrophy. Nature Genet. 21, 285–288 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Novelli, G. et al. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am. J. Hum. Genet. 71, 426–431 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen, L. et al. LMNA mutations in atypical Werner's syndrome. Lancet 362, 440–445 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Fatkin, D. et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N. Engl. J. Med. 341, 1715–1724 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. De Sandre-Giovannoli, A. et al. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot–Marie–Tooth disorder type 2) and mouse. Am. J. Hum. Genet. 70, 726–736 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Eriksson, M. et al. Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423, 293–298 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. De Sandre-Giovannoli, A. et al. Lamin A truncation in Hutchinson–Gilford progeria. Science 300, 2055 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Bione, S. et al. Identification of a novel X-linked gene responsible for Emery–Dreifuss muscular dystrophy. Nature Genet. 8, 323–327 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Koenig, M., Monaco, A. P. & Kunkel, L. M. The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein. Cell 53, 219–226 (1988). One of the groundbreaking papers in the field, which describes the protein product of the dystrophin gene, the first gene associated with MD.

    Article  CAS  PubMed  Google Scholar 

  12. Mokri, B. & Engel, A. G. Duchenne dystrophy: electron microscopic findings pointing to a basic or early abnormality in the plasma membrane of the muscle fiber. Neurology 25, 1111–1120 (1975).

    Article  CAS  PubMed  Google Scholar 

  13. Davies, K. E. et al. Linkage analysis of two cloned DNA sequences flanking the Duchenne muscular dystrophy locus on the short arm of the human X chromosome. Nucleic Acids Res. 11, 2303–2312 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Grum, V. L., Li, D., MacDonald, R. I. & Mondragon, A. Structures of two repeats of spectrin suggest models of flexibility. Cell 98, 523–535 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Pasternak, C., Wong, S. & Elson, E. L. Mechanical function of dystrophin in muscle cells. J. Cell Biol. 128, 355–361 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Hemmings, L., Kuhlman, P. A. & Critchley, D. R. Analysis of the actin-binding domain of α-actinin by mutagenesis and demonstration that dystrophin contains a functionally homologous domain. J. Cell Biol. 116, 1369–1380 (1992).

    Article  CAS  PubMed  Google Scholar 

  17. Rybakova, I. N., Amann, K. J. & Ervasti, J. M. A new model for the interaction of dystrophin with F-actin. J. Cell Biol. 135, 661–672 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Rybakova, I. N. & Ervasti, J. M. Dystrophin–glycoprotein complex is monomeric and stabilizes actin filaments in vitro through a lateral association. J. Biol. Chem. 272, 28771–28778 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Rybakova, I. N., Patel, J. R. & Ervasti, J. M. The dystrophin complex forms a mechanically strong link between the sarcolemma and costameric actin. J. Cell Biol. 150, 1209–1214 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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). Describes four members of the DAPC and illustrates that their expression is diminished in DMD patients, a crucial finding in the understanding of the pathogenesis of dystrophic muscle.

    Article  CAS  PubMed  Google Scholar 

  21. Yoshida, M. & Ozawa, E. Glycoprotein complex anchoring dystrophin to sarcolemma. J. Biochem. (Tokyo) 108, 748–752 (1990).

    Article  CAS  Google Scholar 

  22. Rando, T. A. The dystrophin–glycoprotein complex, cellular signaling, and the regulation of cell survival in the muscular dystrophies. Muscle Nerve 24, 1575–1594 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. 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). Shows that dystrophin-deficient muscle is more susceptible to injury after damage by mechanical stress caused by contraction, supporting the hypothesis that dystrophin reinforces the sarcolemma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Grady, R. M. et al. Role for α-dystrobrevin in the pathogenesis of dystrophin-dependent muscular dystrophies. Nature Cell Biol. 1, 215–220 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Newey, S. E., Benson, M. A., Ponting, C. P., Davies, K. E. & Blake, D. J. Alternative splicing of dystrobrevin regulates the stoichiometry of syntrophin binding to the dystrophin protein complex. Curr. Biol. 10, 1295–1298 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Brenman, J. E. et al. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and α1-syntrophin mediated by PDZ domains. Cell 84, 757–767 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Wehling, M., Spencer, M. J. & Tidball, J. G. A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice. J. Cell Biol. 155, 123–131 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Oak, S. A., Russo, K., Petrucci, T. C. & Jarrett, H. W. Mouse α1-syntrophin binding to Grb2: further evidence of a role for syntrophin in cell signaling. Biochemistry 40, 11270–11278 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Adams, M. E. et al. Absence of α-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin. J. Cell Biol. 150, 1385–1398 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Crosbie, R. H. et al. Mdx muscle pathology is independent of nNOS perturbation. Hum. Mol. Genet. 7, 823–829 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Adams, M. E., Mueller, H. A. & Froehner, S. C. In vivo requirement of the α-syntrophin PDZ domain for the sarcolemmal localization of nNOS and aquaporin-4. J. Cell Biol. 155, 113–122 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Love, D. R. et al. An autosomal transcript in skeletal muscle with homology to dystrophin. Nature 339, 55–58 (1989). The first report about utrophin, an autosomal homologue of dystrophin. This protein has been actively investigated for treatment of MD as its upregulation has been shown to ameliorate dystrophic features.

    Article  CAS  PubMed  Google Scholar 

  33. Crawford, G. E. et al. Assembly of the dystrophin-associated protein complex does not require the dystrophin COOH-terminal domain. J. Cell Biol. 150, 1399–1410 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yoshida, M. et al. Biochemical evidence for association of dystrobrevin with the sarcoglycan–sarcospan complex as a basis for understanding sarcoglycanopathy. Hum. Mol. Genet. 9, 1033–1040 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Mizuno, Y. et al. Desmuslin, an intermediate filament protein that interacts with α-dystrobrevin and desmin. Proc. Natl Acad. Sci. USA 98, 6156–6161 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Benson, M. A., Newey, S. E., Martin-Rendon, E., Hawkes, R. & Blake, D. J. Dysbindin, a novel coiled-coil-containing protein that interacts with the dystrobrevins in muscle and brain. J. Biol. Chem. 276, 24232–24241 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Newey, S. E. et al. Syncoilin, a novel member of the intermediate filament superfamily that interacts with α-dystrobrevin in skeletal muscle. J. Biol. Chem. 276, 6645–6655 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Poon, E., Howman, E. V., Newey, S. E. & Davies, K. E. Association of syncoilin and desmin: linking intermediate filament proteins to the dystrophin-associated protein complex. J. Biol. Chem. 277, 3433–3439 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Ichida, F. et al. Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome. Circulation 103, 1256–1263 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Granger, B. L. & Lazarides, E. Synemin: a new high molecular weight protein associated with desmin and vimentin filaments in muscle. Cell 22, 727–738 (1980).

    Article  CAS  PubMed  Google Scholar 

  41. Bellin, R. M. et al. Molecular characteristics and interactions of the intermediate filament protein synemin. Interactions with α-actinin may anchor synemin-containing heterofilaments. J. Biol. Chem. 274, 29493–29499 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Bhosle, R. C., Michele, D. E., Campbell, K. P., Li, Z. & Robson, R. M. Interactions of intermediate filament protein synemin with dystrophin and utrophin. Biochem. Biophys. Res. Commun. 346, 768–777 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Williamson, R. A. et al. Dystroglycan is essential for early embryonic development: disruption of Reichert's membrane in Dag1-null mice. Hum. Mol. Genet. 6, 831–841 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Cohn, R. D. et al. Disruption of Dag1 in differentiated skeletal muscle reveals a role for dystroglycan in muscle regeneration. Cell 110, 639–648 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Ibraghimov-Beskrovnaya, O. et al. Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix. Nature 355, 696–702 (1992). Describes the dystroglycans and finds that the larger α-dystroglycan is reduced in dystrophin-deficient mice, thereby disrupting the link between dystrophin, the sarcolemma and the ECM.

    Article  CAS  PubMed  Google Scholar 

  46. Michele, D. E. & Campbell, K. P. Dystrophin–glycoprotein complex: post-translational processing and dystroglycan function. J. Biol. Chem. 278, 15457–15460 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Chamberlain, J. S. et al. Interactions between dystrophin and the sarcolemma membrane. Soc. Gen. Physiol. Ser. 52, 19–29 (1997).

    CAS  PubMed  Google Scholar 

  48. Ozawa, E., Mizuno, Y., Hagiwara, Y., Sasaoka, T. & Yoshida, M. Molecular and cell biology of the sarcoglycan complex. Muscle Nerve 32, 563–576 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Laval, S. H. & Bushby, K. M. Limb–girdle muscular dystrophies — from genetics to molecular pathology. Neuropathol. Appl. Neurobiol. 30, 91–105 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Barton, E. R. Impact of sarcoglycan complex on mechanical signal transduction in murine skeletal muscle. Am. J. Physiol. Cell Physiol. 290, C411–C419 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Hayashi, K. et al. Sarcospan: ultrastructural localization and its relation to the sarcoglycan subcomplex. Micron 37, 591–596 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Rafii, M. S. et al. Biglycan binds to α- and γ-sarcoglycan and regulates their expression during development. J. Cell. Physiol. 1 Aug 2006 (doi:10.1002/jcp.20740).

  53. Thompson, T. G. et al. Filamin 2 (FLN2): a muscle-specific sarcoglycan interacting protein. J. Cell Biol. 148, 115–126 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yang, B. et al. SH3 domain-mediated interaction of dystroglycan and Grb2. J. Biol. Chem. 270, 11711–11714 (1995).

    Article  CAS  PubMed  Google Scholar 

  55. Way, M. & Parton, R. G. M-caveolin, a muscle-specific caveolin-related protein. FEBS Lett. 378, 108–112 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. Galbiati, F. et al. Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin–glycoprotein complex, and T-tubule abnormalities. J. Biol. Chem. 276, 21425–21433 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Venema, V. J., Ju, H., Zou, R. & Venema, R. C. Interaction of neuronal nitric-oxide synthase with caveolin-3 in skeletal muscle. Identification of a novel caveolin scaffolding/inhibitory domain. J. Biol. Chem. 272, 28187–28190 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Song, K. S. et al. Expression of caveolin-3 in skeletal, cardiac, and smooth muscle cells. Caveolin-3 is a component of the sarcolemma and co-fractionates with dystrophin and dystrophin-associated glycoproteins. J. Biol. Chem. 271, 15160–15165 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. Scherer, P. E. & Lisanti, M. P. Association of phosphofructokinase-M with caveolin-3 in differentiated skeletal myotubes. Dynamic regulation by extracellular glucose and intracellular metabolites. J. Biol. Chem. 272, 20698–20705 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Galbiati, F. et al. Transgenic overexpression of caveolin-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype. Proc. Natl Acad. Sci. USA 97, 9689–9694 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sotgia, F. et al. Caveolin-3 directly interacts with the C-terminal tail of β-dystroglycan. Identification of a central WW-like domain within caveolin family members. J. Biol. Chem. 275, 38048–38058 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Minetti, C. et al. Mutations in the caveolin-3 gene cause autosomal dominant limb–girdle muscular dystrophy. Nature Genet. 18, 365–368 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Herrmann, R. et al. Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy. Hum. Mol. Genet. 9, 2335–2340 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  65. Galbiati, F., Volonte, D., Minetti, C., Bregman, D. B. & Lisanti, M. P. Limb-girdle muscular dystrophy (LGMD-1C) mutants of caveolin-3 undergo ubiquitination and proteasomal degradation. Treatment with proteasomal inhibitors blocks the dominant negative effect of LGMD-1C mutants and rescues wild-type caveolin-3. J. Biol. Chem. 275, 37702–37711 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Matsuda, C. et al. Dysferlin interacts with affixin (β-parvin) at the sarcolemma. J. Neuropathol. Exp. Neurol. 64, 334–340 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Yamaji, S. et al. Affixin interacts with α-actinin and mediates integrin signaling for reorganization of F-actin induced by initial cell–substrate interaction. J. Cell Biol. 165, 539–551 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lennon, N. J. et al. Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing. J. Biol. Chem. 278, 50466–50473 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Holt, K. H., Crosbie, R. H., Venzke, D. P. & Campbell, K. P. Biosynthesis of dystroglycan: processing of a precursor propeptide. FEBS Lett. 468, 79–83 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Barresi, R. & Campbell, K. P. Dystroglycan: from biosynthesis to pathogenesis of human disease. J. Cell Sci. 119, 199–207 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Kobayashi, K. et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394, 388–392 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Beltran-Valero de Bernabe, D. et al. Mutations in the FKRP gene can cause muscle–eye–brain disease and Walker–Warburg syndrome. J. Med. Genet. 41, e61 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Taniguchi, K. et al. Worldwide distribution and broader clinical spectrum of muscle–eye–brain disease. Hum. Mol. Genet. 12, 527–534 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Beltran-Valero de Bernabe, D. et al. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker–Warburg syndrome. Am. J. Hum. Genet. 71, 1033–1043 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Brockington, M. et al. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin α2 deficiency and abnormal glycosylation of α-dystroglycan. Am. J. Hum. Genet. 69, 1198–1209 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Longman, C. et al. Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of α-dystroglycan. Hum. Mol. Genet. 12, 2853–2861 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Brockington, M. et al. Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum. Mol. Genet. 10, 2851–2859 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Kanagawa, M. et al. Molecular recognition by LARGE is essential for expression of functional dystroglycan. Cell 117, 953–964 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Yoshida, A. et al. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev. Cell 1, 717–724 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Endo, T. O-Mannosyl glycans in mammals. Biochim. Biophys. Acta 1473, 237–246 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Esapa, C. T. et al. Functional requirements for fukutin-related protein in the Golgi apparatus. Hum. Mol. Genet. 11, 3319–3331 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Saito, Y., Mizuguchi, M., Oka, A. & Takashima, S. Fukutin protein is expressed in neurons of the normal developing human brain but is reduced in Fukuyama-type congenital muscular dystrophy brain. Ann. Neurol. 47, 756–764 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Ishii, H., Hayashi, Y. K., Nonaka, I. & Arahata, K. Electron microscopic examination of basal lamina in Fukuyama congenital muscular dystrophy. Neuromuscul. Disord. 7, 191–197 (1997).

    Article  CAS  PubMed  Google Scholar 

  84. Topaloglu, H. et al. FKRP gene mutations cause congenital muscular dystrophy, mental retardation, and cerebellar cysts. Neurology 60, 988–992 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Brown, S. C. et al. Abnormalities in α-dystroglycan expression in MDC1C and LGMD2I muscular dystrophies. Am. J. Pathol. 164, 727–737 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Manya, H. et al. Demonstration of mammalian protein O-mannosyltransferase activity: coexpression of POMT1 and POMT2 required for enzymatic activity. Proc. Natl Acad. Sci. USA 101, 500–505 (2004).

    CAS  PubMed  Google Scholar 

  87. van Reeuwijk, J. et al. The expanding phenotype of POMT1 mutations: from Walker–Warburg syndrome to congenital muscular dystrophy, microcephaly, and mental retardation. Hum. Mutat. 27, 453–459 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. von der Mark, H. et al. Skeletal myoblasts utilize a novel β1-series integrin and not α6β1 for binding to the E8 and T8 fragments of laminin. J. Biol. Chem. 266, 23593–23601 (1991).

    CAS  PubMed  Google Scholar 

  89. Gontier, Y. et al. The Z-disc proteins myotilin and FATZ-1 interact with each other and are connected to the sarcolemma via muscle-specific filamins. J. Cell Sci. 118, 3739–3749 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Mayer, U. et al. Absence of integrin α7 causes a novel form of muscular dystrophy. Nature Genet. 17, 318–323 (1997).

    Article  CAS  PubMed  Google Scholar 

  91. Horwitz, A., Duggan, K., Buck, C., Beckerle, M. C. & Burridge, K. Interaction of plasma membrane fibronectin receptor with talin — a transmembrane linkage. Nature 320, 531–533 (1986).

    Article  CAS  PubMed  Google Scholar 

  92. Hodges, B. L. et al. Altered expression of the α7β1 integrin in human and murine muscular dystrophies. J. Cell Sci. 110, 2873–2881 (1997).

    CAS  PubMed  Google Scholar 

  93. Burkin, D. J., Wallace, G. Q., Nicol, K. J., Kaufman, D. J. & Kaufman, S. J. Enhanced expression of the α7β1 integrin reduces muscular dystrophy and restores viability in dystrophic mice. J. Cell Biol. 152, 1207–1218 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Allikian, M. J., Hack, A. A., Mewborn, S., Mayer, U. & McNally, E. M. Genetic compensation for sarcoglycan loss by integrin α7β1 in muscle. J. Cell Sci. 117, 3821–3830 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Laing, N. G. & Nowak, K. J. When contractile proteins go bad: the sarcomere and skeletal muscle disease. Bioessays 27, 809–822 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Gregorio, C. C. et al. The NH2 terminus of titin spans the Z-disc: its interaction with a novel 19-kD ligand (T-cap) is required for sarcomeric integrity. J. Cell Biol. 143, 1013–1027 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Nicholas, G. et al. Titin-cap associates with, and regulates secretion of, Myostatin. J. Cell Physiol. 193, 120–131 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Vainzof, M. et al. Telethonin protein expression in neuromuscular disorders. Biochim. Biophys. Acta 1588, 33–40 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. Mayans, O. et al. Structural basis for activation of the titin kinase domain during myofibrillogenesis. Nature 395, 863–869 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. Zou, P. et al. Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk. Nature 439, 229–233 (2006). Describes how two titin proteins form an antiparallel sandwich with one telethonin molecule, providing insight into how sarcomeres are anchored and crosslinked and perhaps explaining the mechanical stability of the Z-line.

    Article  CAS  PubMed  Google Scholar 

  101. Richard, I. et al. Mutations in the proteolytic enzyme calpain 3 cause limb–girdle muscular dystrophy type 2A. Cell 81, 27–40 (1995). The first description that mutations within an enzyme, calpain-3, rather than a predominantly structural protein, cause MD.

    Article  CAS  PubMed  Google Scholar 

  102. Guyon, J. R. et al. Calpain 3 cleaves filamin C and regulates its ability to interact with γ- and δ-sarcoglycans. Muscle Nerve 28, 472–483 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. van der Ven, P. F. et al. Indications for a novel muscular dystrophy pathway. γ-filamin, the muscle-specific filamin isoform, interacts with myotilin. J. Cell Biol. 151, 235–248 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Haravuori, H. et al. Secondary calpain3 deficiency in 2q-linked muscular dystrophy: titin is the candidate gene. Neurology 56, 869–877 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Baghdiguian, S. et al. Calpain 3 deficiency is associated with myonuclear apoptosis and profound perturbation of the IκBα/NF-κB pathway in limb–girdle muscular dystrophy type 2A. Nature Med. 5, 503–511 (1999).

    Article  CAS  PubMed  Google Scholar 

  106. Kramerova, I., Kudryashova, E., Tidball, J. G. & Spencer, M. J. Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro. Hum. Mol. Genet. 13, 1373–1388 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Kudryashova, E., Kudryashov, D., Kramerova, I. & Spencer, M. J. Trim32 is a ubiquitin ligase mutated in limb girdle muscular dystrophy type 2H that binds to skeletal muscle myosin and ubiquitinates actin. J. Mol. Biol. 354, 413–424 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Salmikangas, P. et al. Myotilin, the limb–girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly. Hum. Mol. Genet. 12, 189–203 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Salmikangas, P. et al. Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb–girdle muscular dystrophy. Hum. Mol. Genet. 8, 1329–1336 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Faulkner, G. et al. ZASP: a new Z-band alternatively spliced PDZ-motif protein. J. Cell Biol. 146, 465–475 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ozawa, R. et al. Emerin-lacking mice show minimal motor and cardiac dysfunctions with nuclear-associated vacuoles. Am. J. Pathol. 168, 907–917 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Vaughan, A. et al. Both emerin and lamin C depend on lamin A for localization at the nuclear envelope. J. Cell Sci. 114, 2577–2590 (2001).

    CAS  PubMed  Google Scholar 

  113. Yates, J. R. et al. Genotype–phenotype analysis in X-linked Emery–Dreifuss muscular dystrophy and identification of a missense mutation associated with a milder phenotype. Neuromuscul. Disord. 9, 159–165 (1999).

    Article  CAS  PubMed  Google Scholar 

  114. Fidzianska, A. & Hausmanowa-Petrusewicz, I. Architectural abnormalities in muscle nuclei. Ultrastructural differences between X-linked and autosomal dominant forms of EDMD. J. Neurol. Sci. 210, 47–51 (2003).

    Article  PubMed  Google Scholar 

  115. Melcon, G. et al. Loss of emerin at the nuclear envelope disrupts the Rb1/E2F and MyoD pathways during muscle regeneration. Hum. Mol. Genet. 15, 637–651 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. Bakay, M. et al. Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb–MyoD pathways in muscle regeneration. Brain 129, 996–1013 (2006). Shows that mutations in two genes, one encoding the nuclear-envelope proteins lamin A and lamin C and one encoding emerin, lead to similar MDs that involve the Rb1 and MyoD transcriptional regulatory pathway. These MDs are similar to another MD, FSHD, which is also thought to involve perturbations of the nuclear envelope.

    Article  PubMed  Google Scholar 

  117. Frock, R. L. et al. Lamin A/C and emerin are critical for skeletal muscle satellite cell differentiation. Genes Dev. 20, 486–500 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Mahadevan, M. et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255, 1253–1255 (1992).

    Article  CAS  PubMed  Google Scholar 

  119. Liquori, C. L. et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293, 864–867 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Day, J. W. & Ranum, L. P. RNA pathogenesis of the myotonic dystrophies. Neuromuscul. Disord. 15, 5–16 (2005).

    Article  PubMed  Google Scholar 

  121. Brais, B. et al. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nature Genet. 18, 164–167 (1998).

    Article  CAS  PubMed  Google Scholar 

  122. Wahle, E. A novel poly(A)-binding protein acts as a specificity factor in the second phase of messenger RNA polyadenylation. Cell 66, 759–768 (1991).

    Article  CAS  PubMed  Google Scholar 

  123. Calado, A., Kutay, U., Kuhn, U., Wahle, E. & Carmo-Fonseca, M. Deciphering the cellular pathway for transport of poly(A)-binding protein II. RNA 6, 245–256 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Davies, J. E., Berger, Z. & Rubinsztein, D. C. Oculopharyngeal muscular dystrophy: potential therapies for an aggregate-associated disorder. Int. J. Biochem. Cell Biol. 38, 1457–1462 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Hewitt, J. E. et al. Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy. Hum. Mol. Genet. 3, 1287–1295 (1994).

    Article  CAS  PubMed  Google Scholar 

  126. van der Maarel, S. M. & Frants, R. R. The D4Z4 repeat-mediated pathogenesis of facioscapulohumeral muscular dystrophy. Am. J. Hum. Genet. 76, 375–386 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Gabellini, D. et al. Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1. Nature 439, 973–977 (2006). The first indication that, in mice, the transgenic overexpression of a gene, FRG1 , which neighbours a repeat-element region, can lead to an MD that is phenotypically similar to human FSHD. These findings reveal a possible mechanism behind the human disease.

    Article  CAS  PubMed  Google Scholar 

  128. Chakkalakal, J. V., Thompson, J., Parks, R. J. & Jasmin, B. J. Molecular, cellular, and pharmacological therapies for Duchenne/Becker muscular dystrophies. FASEB J. 19, 880–891 (2005).

    Article  CAS  PubMed  Google Scholar 

  129. Nowak, K. J. & Davies, K. E. Duchenne muscular dystrophy and dystrophin: pathogenesis and opportunities for treatment. EMBO Rep. 5, 872–876 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Blankinship, M. J., Gregorevic, P. & Chamberlain, J. S. Gene therapy strategies for Duchenne muscular dystrophy utilizing recombinant adeno-associated virus vectors. Mol. Ther. 13, 241–249 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Wilton, S. D. & Fletcher, S. Modification of pre-mRNA processing: application to dystrophin expression. Curr. Opin. Mol. Ther. 8, 130–135 (2006).

    CAS  PubMed  Google Scholar 

  132. Alter, J. et al. Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nature Med. 12, 175–177 (2006). Outlines the delivery of morpholino oligonucleotides through an intravenous injection in a dystrophic mouse model, resulting in body-wide expression of dystrophin and improvement in muscle function.

    Article  CAS  PubMed  Google Scholar 

  133. Zhu, T. et al. Sustained whole-body functional rescue in congestive heart failure and muscular dystrophy hamsters by systemic gene transfer. Circulation 112, 2650–2659 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Denti, M. A. et al. Body-wide gene therapy of Duchenne muscular dystrophy in the mdx mouse model. Proc. Natl Acad. Sci. USA 103, 3758–3763 (2006). An exciting description of body-wide delivery of a small nuclear RNA through transduction of an AAV in a dystrophic mouse model, which led to persistent exon skipping of dystrophin and subsequent recovery of functional and biochemical parameters.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

K.E.D. is supported by the Medical Research Council, UK, Muscular Dystrophy Association, USA, the Muscular Dystrophy Campaign, UK, and the Association Française Contre les Myopathies. K.J.N. is funded by the Australian National Health and Medical Research Council.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Related links

Related links

DATABASES

OMIM

BMD

DM1

DM2

DMD

EDMD

Hutchinson–Gilford progeria

LGMD2J

TMD

FURTHER INFORMATION

Kay Davies' homepage

Glossary

Sarcolemma

The muscle-cell membrane.

Myofibre

An individual skeletal-muscle cell that consists of several nuclei formed by the fusion of myoblasts. Also known as a myocyte.

Sarcoplasm

The cytoplasm of a striated-muscle fibre.

Sarcoplasmic reticulum

Modified endoplasmic reticulum of muscle cells that is adapted to contain large stores of Ca2+- that can be released readily to initiate contraction on receiving signals relayed by the T-tubules.

Transverse (T)-tubule

A deep invagination of the plasma membrane of striated-muscle cells that extends perpendicularly from the surface. Muscle contraction occurs when depolarization of the T-tubule membrane triggers the release of Ca2+ from the sarcoplasmic reticulum.

Sarcomere

The fundamental unit of muscle contraction, which extends from one Z-line to another.

Costamere

An assembly of sub-sarcolemmal proteins that physically connects the Z-disk of the sarcomere of peripheral myofibrils to the sarcolemma and the basement membrane.

Myotendinous junction

The junction of muscle fibres and tendons.

Neuromuscular junction

The junction of a motor neuron with a muscle fibre.

Spectrin superfamily

Closely related protein members that bind to actin and contain differing numbers of tandem homologous repeats comprised of a three-α-helix motif.

Satellite cell

A myogenic stem cell that is located under the basement membrane of muscle fibres.

Syntrophin

A family that consists of widely expressed adaptor proteins, which are highly concentrated at the postsynaptic membrane of the NMJ (similar to dystrophin).

Laminins

A family of glycoproteins that makes up the main non-collagenous component of the basement membrane. One type of laminin, laminin-2, is found in the brain and muscle fibres. Laminin-2 is composed of an α2, β1 and γ1 chain. In muscle, one end of laminin-2 binds to α-dystroglycan and the other end binds to the ECM.

Sarcoglycan complex

A sub-complex within the dystrophin-associated protein complex composed of four glycosylated transmembrane proteins each with a short intracellular domain, a single transmembrane region and a large extracellular domain.

Caveolae

Small invaginations of the plasma membrane that are associated with the control of signal-transduction events.

Ferlin protein family

Family of proteins with a C-terminal transmembrane domain and four to seven C2 domains. These proteins mediate fusion and vesicle trafficking in a Ca2+-dependent manner.

Myoblast

An undifferentiated, mononucleated cell that is a precursor of a muscle cell.

Basement membrane

Amorphous extracellular matrix material, composed of proteins such as collagen, laminin and fibronectin, that surrounds individual muscle fibres. It is comprised of two layers, the basal lamina and the reticular lamina.

Myofibrillogenesis

The transition from premyofibril to myofibril, which is a long, highly organized bundle of contractile proteins or filaments in the sarcoplasm of the myofibre.

Z-line streaming

A common pathological feature in which the dense Z-line material extends into one or both of the adjacent I-bands and, in advanced cases, into the whole sarcomere.

PDZ motif

Protein–protein interaction domain that is thought to have a role in directing intracellular proteins to several protein complexes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Davies, K., Nowak, K. Molecular mechanisms of muscular dystrophies: old and new players. Nat Rev Mol Cell Biol 7, 762–773 (2006). https://doi.org/10.1038/nrm2024

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2024

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing