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:

Pharmacological strategies for muscular dystrophy

Nature Reviews Drug Discovery volume 2, pages 379–390 (2003)Cite this article

Key Points

  • Duchenne muscular dystrophy (DMD) is the most common X-linked neuromuscular disease. It is caused by mutations in the DMD gene that lead to abnormalities of dystrophin protein expression in muscle. DMD is fatal and currently incurable.

  • Well-characterized animal models for DMD exist, as do well-characterized and sensitive anatomical, biochemical and physiological methods for evaluating a therapeutic intervention in animal models of DMD.

  • Gene therapy approaches (using both vector and vectorless strategies), as well as cell-based therapies (using myoblasts and stem cells) have met with some success in pre-clinical studies. They currently face a number of technical challenges.

  • Pharmacological strategies can circumvent many of the hurdles that currently hamper gene- and cell-based therapies.

  • This review covers a number of promising pharmacological strategies such as steroids, maintaining calcium homeostasis, decreasing inflammation, increasing muscle strength, suppressing stop codons, upregulation of utrophin, and increasing muscle mass via modulation of growth/developmental factors.

  • Strategies associated with utrophin upregulation and increasing muscle mass via modulation of growth/developmental factors are covered in some detail.

Abstract

Duchenne muscular dystrophy (DMD) is a fatal, genetic disorder whose relentless progression underscores the urgency for developing a cure. Although Duchenne initiated clinical trials roughly 150 years ago, therapies for DMD remain supportive rather than curative. A paradigm shift towards developing rational therapeutic strategies occurred with identification of the DMD gene. Gene- and cell-based therapies designed to replace the missing gene and/or dystrophin protein have achieved varying degrees of success. However, pharmacological strategies not designed to replace dystrophin per se appear promising, and can circumvent many hurdles hampering gene- and cell-based therapy. Here, we will review present pharmacological strategies, in particular those dealing with functional substitution of dystrophin by utrophin and enhancing muscle progenitor commitment by myostatin blockade, with a view toward facilitating drug discovery for DMD.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: The muscular dystrophies and organization of the dystrophin–glycoprotein complex.
Figure 2: Identified dystrophin and utrophin human isoforms and associated promoters.
Figure 3: Model for transcriptional activation of the utrophin promoter A.
Figure 4: Schematic overview of high-throughput utrophin promoter screening.
Figure 5: Model for myostatin processing and pharmacological blockade.

Similar content being viewed by others

References

  1. Duchenne, G. B. A. Recherches sur la paralysie musculaire pseudohypertrophique ou paralysie myo-sclerosique. Arch. Gen. Med. 11, 5–528 (1868).

    Google Scholar 

  2. Monaco, A. P. et al. Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene. Nature 323, 646–650 (1986).

    Article  CAS  PubMed  Google Scholar 

  3. Hoffman, E. P., Brown, R. H. & Kunkel, L. M. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51, 919–928 (1987).

    Article  CAS  PubMed  Google Scholar 

  4. Koenig, M., Monaco, A. P. & Kunkel, L. M. The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein. Cell 53, 219–226 (1988). References 1–4 are classic papers describing DMD and elucidating its cause.

    Article  CAS  PubMed  Google Scholar 

  5. Love, D. R. et al. An autosomal transcript in skeletal muscle with homology to dystrophin. Nature 339, 55–58 (1989).

    Article  CAS  PubMed  Google Scholar 

  6. Khurana, T. S., Hoffman, E. P. & Kunkel, L. M. Identification of a chromosome 6-encoded dystrophin-related protein. J. Biol. Chem. 265, 16717–16720 (1990).

    Article  CAS  PubMed  Google Scholar 

  7. Tinsley, J. M. et al. Primary structure of dystrophin-related protein. Nature 360, 591–593 (1992). References 5–7 describe the identification of the dystrophin-related protein utrophin.

    Article  CAS  PubMed  Google Scholar 

  8. Roberts, R. G. et al. Characterization of DRP2, a novel human dystrophin homologue. Nature Genet. 13, 223–226 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Khurana, T. S. et al. (CA) repeat polymorphism in the chromosome 18 encoded dystrophin-like protein. Hum. Mol. Genet. 3, 841 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Sadoulet, P. H., Khurana, T. S., Cohen, J. B. & Kunkel, L. M. Cloning and characterization of the human homologue of a dystrophin related phosphoprotein found at the Torpedo electric organ post-synaptic membrane. Hum. Mol. Genet. 5, 489–496 (1996).

    Article  Google Scholar 

  11. Blake, D. J., Nawrotzki, R., Peters, M. F., Froehner, S. C. & Davies, K. E. Isoform diversity of dystrobrevin, the murine 87-kDa postsynaptic protein. J. Biol. Chem. 271, 7802–7810 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Campbell, K. P. Three muscular dystrophies: loss of cytoskeletal extracellular matrix linkage. Cell 80, 675–679 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Ervasti, J. M. & Campbell, K. P. Membrane organization of the dystrophin–glycoprotein complex. Cell 66, 1121–1131 (1991).

    Article  CAS  PubMed  Google Scholar 

  14. Matsumura, K., Ervasti, J. M., Ohlendieck, K., Kahl, S. D. & Campbell, K. P. Association of dystrophin-related protein with dystrophin-associated proteins in mdx mouse muscle. Nature 360, 588–591 (1992).

    Article  CAS  PubMed  Google Scholar 

  15. Emery, A. E. H. Duchenne Muscular Dystrophy (Oxford University Press, 1993).

    Google Scholar 

  16. Engel, A. G. & Franzini-Armstrong, C. Myology (McGraw–Hill, New York, 1994).

    Google Scholar 

  17. Karpati, G. & Carpenter, S. Small-calibre skeletal muscle fibers do not suffer deleterious consequences of dystrophic gene expression. Am. J. Med. Genet. 25, 653–658 (1986).

    Article  CAS  PubMed  Google Scholar 

  18. Kaminski, H. J., al-Hakim, M., Leigh, R. J., Katirji, M. B. & Ruff, R. L. Extraocular muscles are spared in advanced Duchenne dystrophy. Ann. Neurol. 32, 586–588 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. Khurana, T. S. et al. Absence of extraocular muscle pathology in Duchenne's muscular dystrophy: role for calcium homeostasis in extraocular muscle sparing. J. Exp. Med. 182, 467–475 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Allamand, V. & Campbell, K. P. Animal models for muscular dystrophy: valuable tools for the development of therapies. Hum. Mol. Genet. 9, 2459–2467 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Bulfield, G., Siller, W. G., Wight, P. A. & Moore, K. J. X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc. Natl Acad. Sci. USA 81, 1189–1192 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cooper, B. J. et al. The homologue of the Duchenne locus is defective in X-linked muscular dystrophy of dogs. Nature 334, 154–156 (1988).

    Article  CAS  PubMed  Google Scholar 

  23. Carpenter, J. L. et al. Feline muscular dystrophy with dystrophin deficiency. Am. J. Pathol. 135, 909–919 (1989). References 21–23 identified genuine animal models for DMD that are invaluable for preclinical therapeutic studies.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Schatzberg, S. J. et al. Molecular analysis of a spontaneous dystrophin 'knockout' dog. Neuromuscul. Disord. 9, 289–295 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Chapman, V. M., Miller, D. R., Armstrong, D. & Caskey, C. T. Recovery of induced mutations for X chromosome-linked muscular dystrophy in mice. Proc. Natl Acad. Sci. USA 86, 1292–1296 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Stedman, H. H. et al. The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy. Nature 352, 536–539 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. Moens, P., Baatsen, P. H. & Marechal, G. Increased susceptibility of EDL muscles from mdx mice to damage induced by contractions with stretch. J. Muscle Res. Cell Motil. 14, 446–451 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. 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). References 26–28 characterize functional deficits in mdx muscle and provide ex vivo experimental paradigms for evaluation of therapeutic interventions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gillis, J. M. & Deconinck, N. The physiological evaluation of gene therapies of dystrophin-deficient muscles. Adv. Exp. Med. Biol. 453, 411–416; discussion 417 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Krag, T. O., Gyrd-Hansen, M. & Khurana, T. S. Harnessing the potential of dystrophin-related proteins for ameliorating Duchenne's muscular dystrophy. Acta Physiol. Scand. 171, 349–358 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Gillis, J. M. Multivariate evaluation of the functional recovery obtained by the overexpression of utrophin in skeletal muscles of the mdx mouse. Neuromuscul. Disord. 12 Suppl. 1, 90–94 (2002).

    Article  Google Scholar 

  32. Deconinck, A. E. et al. Utrophin–dystrophin-deficient mice as a model for Duchenne muscular dystrophy. Cell 90, 717–727 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Grady, R. M. et al. Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy. Cell 90, 729–738 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Morrison, J., Lu, Q. L., Pastoret, C., Partridge, T. & Bou-Gharios, G. T-cell-dependent fibrosis in the mdx dystrophic mouse. Lab. Invest. 80, 881–891 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Keep, N. H., Norwood, F. L., Moores, C. A., Winder, S. J. & Kendrick-Jones, J. The 2.0 A structure of the second calponin homology domain from the actin-binding region of the dystrophin homologue utrophin. J. Mol. Biol. 285, 1257–1264 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Winder, S. J. et al. Utrophin actin binding domain: analysis of actin binding and cellular targeting. J. Cell Sci. 108, 63–71 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Winder, S. J., Gibson, T. J. & Kendrick, J. J. Dystrophin and utrophin: the missing links. FEBS Lett. 369, 27–33 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Blake, D. J., Weir, A., Newey, S. E. & Davies, K. E. Function and genetics of dystrophin and dystrophin-related proteins in muscle. Physiol. Rev. 82, 291–329 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. 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 

  40. Love, D. R. et al. Tissue distribution of the dystrophin-related gene product and expression in the mdx and dy mouse. Proc. Natl Acad. Sci. USA 88, 3243–3247 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Khurana, T. S. et al. Immunolocalization and developmental expression of dystrophin related protein in skeletal muscle. Neuromuscul. Disord. 1, 185–194 (1991).

    Article  CAS  PubMed  Google Scholar 

  42. Nguyen, T. M. et al. Localization of the DMDL gene-encoded dystrophin-related protein using a panel of nineteen monoclonal antibodies: presence at neuromuscular junctions, in the sarcolemma of dystrophic skeletal muscle, in vascular and other smooth muscles, and in proliferating brain cell lines. J. Cell Biol. 115, 1695–1700 (1991).

    Article  CAS  PubMed  Google Scholar 

  43. Ohlendieck, K. et al. Dystrophin-related protein is localized to neuromuscular junctions of adult skeletal muscle. Neuron 7, 499–508 (1991).

    Article  CAS  PubMed  Google Scholar 

  44. Byers, T. J., Kunkel, L. M. & Watkins, S. C. The sub-cellular distribution of dystrophin in mouse skeletal, cardiac, and smooth muscle. J. Cell Biol. 115, 411–421 (1991).

    Article  CAS  PubMed  Google Scholar 

  45. Bewick, G. S., Nicholson, L. V., Young, C., O'Donnell, E. & Slater, C. R. Different distributions of dystrophin and related proteins at nerve-muscle junctions. Neuroreport 3, 857–860 (1992).

    Article  CAS  PubMed  Google Scholar 

  46. Clerk, A., Morris, G. E., Dubowitz, V., Davies, K. E. & Sewry, C. A. Dystrophin-related protein, utrophin, in normal and dystrophic human fetal skeletal muscle. Histochem. J. 25, 554–561 (1993).

    Article  CAS  PubMed  Google Scholar 

  47. Pons, F., Nicholson, L. V., Robert, A., Voit, T. & Leger, J. J. Dystrophin and dystrophin-related protein (utrophin) distribution in normal and dystrophin-deficient skeletal muscles. Neuromuscul. Disord. 3, 507–514 (1993).

    Article  CAS  PubMed  Google Scholar 

  48. Radojevic, V., Lin, S. & Burgunder, J. M. Differential expression of dystrophin, utrophin, and dystrophin-associated proteins in human muscle culture. Cell Tissue Res. 300, 447–457 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Deconinck, A. E. et al. Postsynaptic abnormalities at the neuromuscular junctions of utrophin-deficient mice. J. Cell. Biol. 136, 883–894 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Grady, R. M., Merlie, J. P. & Sanes, J. R. Subtle neuromuscular defects in utrophin-deficient mice. J. Cell. Biol. 136, 871–882 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rafael, J. A., Tinsley, J. M., Potter, A. C., Deconinck, A. E. & Davies, K. E. Skeletal muscle-specific expression of a utrophin transgene rescues utrophin-dystrophin deficient mice. Nature Genet. 19, 79–82 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Tinsley, J. et al. Expression of full-length utrophin prevents muscular dystrophy in mdx mice. Nature Med. 4, 1441–1444 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Tinsley, J. M. et al. Amelioration of the dystrophic phenotype of mdx mice using a truncated utrophin transgene. Nature 384, 349–353 (1996). Reference 53 provides the proof of principle that utrophin can functionally substitute for dystrophin in vivo.

    Article  CAS  PubMed  Google Scholar 

  54. Wakefield, P. M. et al. Prevention of the dystrophic phenotype in dystrophin/utrophin-deficient muscle following adenovirus-mediated transfer of a utrophin minigene. Gene Ther. 7, 201–204 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Pearce, M. et al. The utrophin and dystrophin genes share similarities in genomic structure. Hum. Mol. Genet. 2, 1765–1772 (1993).

    Article  CAS  PubMed  Google Scholar 

  56. Jimenez-Mallebrera, C., Davies, K., Putt, W. & Edwards, Y. H. A study of short utrophin isoforms in mice deficient for full-length utrophin. Mamm. Genome 14, 47–60 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Dennis, C. L., Tinsley, J. M., Deconinck, A. E. & Davies, K. E. Molecular and functional analysis of the utrophin promoter. Nucleic Acids Res. 24, 1646–1652 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Burton, E. A., Tinsley, J. M., Holzfeind, P. J., Rodrigues, N. R. & Davies, K. E. A second promoter provides an alternative target for therapeutic up-regulation of utrophin in Duchenne muscular dystrophy. Proc. Natl Acad. Sci. USA 96, 14025–14030 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Galvagni, F. & Oliviero, S. Utrophin transcription is activated by an intronic enhancer. J. Biol. Chem. 275, 3168–3172 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Weir, A. P., Burton, E. A., Harrod, G. & Davies, K. E. A- and B-utrophin have different expression patterns and are differentially up-regulated in mdx muscle. J. Biol. Chem. 277, 45285–45290 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Schaeffer, L., de Kerchove d'Exaerde, A. & Changeux, J. P. Targeting transcription to the neuromuscular synapse. Neuron 31, 15–22 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Buonanno, A. & Fischbach, G. D. Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr. Opin. Neurobiol. 11, 287–296 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Gramolini, A. O. et al. Induction of utrophin gene expression by heregulin in skeletal muscle cells: role of the N-box motif and GA binding protein. Proc. Natl Acad. Sci. USA 96, 3223–3227 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Khurana, T. S. et al. Activation of utrophin promoter by heregulin via the ets-related transcription factor complex GA-binding protein α/β. Mol. Biol. Cell. 10, 2075–2086 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Galvagni, F., Capo, S. & Oliviero, S. Sp1 and Sp3 physically interact and co-operate with GABP for the activation of the utrophin promoter. J. Mol. Biol. 306, 985–996 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Perkins, K. J., Burton, E. A. & Davies, K. E. The role of basal and myogenic factors in the transcriptional activation of utrophin promoter A: implications for therapeutic up-regulation in Duchenne muscular dystrophy. Nucleic Acids Res. 29, 4843–4850 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Gyrd-Hansen, M., Krag, T. O., Rosmarin, A. G. & Khurana, T. S. Sp1 and the ets-related transcription factor complex GABP α/β functionally cooperate to activate the utrophin promoter. J. Neurol. Sci. 197, 27–35 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Perkins, K. J. & Davies, K. E. Ets, Ap-1 and GATA factor families regulate the utrophin B promoter; potential regulatory mechanisms for endothelial-specific expression. FEBS Lett. 538, 168–172 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Briguet, A., Bleckmann, D., Bettan, M., Mermod, N. & Meier, T. Transcriptional activation of the utrophin promoter B by a constitutively active Ets-transcription factor. Neuromuscul. Disord. 13, 143–150 (2003).

    Article  PubMed  Google Scholar 

  70. Chaubourt, E. et al. Nitric oxide and l-arginine cause an accumulation of utrophin at the sarcolemma: a possible compensation for dystrophin loss in Duchenne muscular dystrophy. Neurobiol. Dis. 6, 499–507 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Chaubourt, E. et al. Muscular nitric oxide synthase (muNOS) and utrophin. J. Physiol. Paris 96, 43–52 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. 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 

  73. Nguyen, H. H., Jayasinha, V., Xia, B., Hoyte, K. & Martin, P. T. Overexpression of the cytotoxic T cell GalNAc transferase in skeletal muscle inhibits muscular dystrophy in mdx mice. Proc. Natl Acad. Sci. USA 99, 5616–5621 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gramolini, A. O., Belanger, G., Thompson, J. M., Chakkalakal, J. V. & Jasmin, B. J. Increased expression of utrophin in a slow vs. a fast muscle involves posttranscriptional events. Am. J. Physiol. Cell. Physiol. 281, C1300–C1309 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Courdier-Fruh, I., Barman, L., Briguet, A. & Meier, T. Glucocorticoid-mediated regulation of utrophin levels in human muscle fibers. Neuromuscul. Disord. 12, S95–S104 (2002).

    Article  PubMed  Google Scholar 

  76. Fisher, R. et al. Non-toxic ubiquitous over-expression of utrophin in the mdx mouse. Neuromuscul. Disord. 11, 713–721 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Squire, S. et al. Prevention of pathology in mdx mice by expression of utrophin: analysis using an inducible transgenic expression system. Hum. Mol. Genet. 11, 3333–3344 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Cerletti, M. et al. The dystrophic phenotype of canine X-linked muscular dystrophy is mitigated by adenovirus-mediated utrophin gene transfer. Gene Ther. (In the press).

  79. Thioudellet, C., Blot, S., Squiban, P., Fardeau, M. & Braun, S. Current protocol of a research phase I clinical trial of full-length dystrophin plasmid DNA in Duchenne/Becker muscular dystrophies. Part I: rationale. Neuromuscul. Disord. 12, S49–S51 (2002).

    Article  PubMed  Google Scholar 

  80. Romero, N. B. et al. Current protocol of a research phase I clinical trial of full-length dystrophin plasmid DNA in Duchenne/Becker muscular dystrophies. Part II: clinical protocol. Neuromuscul. Disord. 12, S45–S48 (2002).

    Article  PubMed  Google Scholar 

  81. Barthelmai, W. On the effect of corticoid administration on creatine phosphokinase in progressive muscular dystrophy. Verh. Dtsch Ges. Inn. Med. 71, 624–626 (1965).

    CAS  PubMed  Google Scholar 

  82. Drachman, D. B., Toyka, K. V. & Myer, E. Prednisone in Duchenne muscular dystrophy. Lancet 2, 1409–1412 (1974). References 81–82 describe the use of steroids in pharmacological therapy of DMD.

    Article  CAS  PubMed  Google Scholar 

  83. Mendell, J. R. et al. Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy. N. Engl. J. Med. 320, 1592–1597 (1989).

    Article  CAS  PubMed  Google Scholar 

  84. Sansome, A., Royston, P. & Dubowitz, V. Steroids in Duchenne muscular dystrophy; pilot study of a new low-dosage schedule. Neuromuscul. Disord. 3, 567–569 (1993).

    Article  CAS  PubMed  Google Scholar 

  85. Bonifati, M. D. et al. A multicenter, double-blind, randomized trial of deflazacort versus prednisone in Duchenne muscular dystrophy. Muscle Nerve 23, 1344–1347 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Manzur, A. Y. in The Muscular Dystrophies (ed. Emery, A. E. H.) 223–246 (Oxford University Press, 2001).

    Google Scholar 

  87. Bodensteiner, J. B. & Engel, A. G. Intracellular calcium accumulation in Duchenne dystrophy and other myopathies: a study of 567,000 muscle fibers in 114 biopsies. Neurology 28, 439–446 (1978).

    Article  CAS  PubMed  Google Scholar 

  88. Fischer, M. D. et al. Expression profiling reveals metabolic and structural components of extraocular muscles. Physiol. Genomics 9, 71–84 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Fong, P. Y., Turner, P. R., Denetclaw, W. F. & Steinhardt, R. A. Increased activity of calcium leak channels in myotubes of Duchenne human and mdx mouse origin. Science 250, 673–676 (1990).

    Article  CAS  PubMed  Google Scholar 

  90. Turner, P. R., Schultz, R., Ganguly, B. & Steinhardt, R. A. Proteolysis results in altered leak channel kinetics and elevated free calcium in mdx muscle. J. Membr. Biol. 133, 243–251 (1993).

    Article  CAS  PubMed  Google Scholar 

  91. De Backer, F., Vandebrouck, C., Gailly, P. & Gillis, J. M. Long-term study of Ca2+ homeostasis and of survival in collagenase-isolated muscle fibres from normal and mdx mice. J. Physiol. 542, 855–865 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bertorini, T. E. et al. Effect of dantrolene in Duchenne muscular dystrophy. Muscle Nerve 14, 503–507 (1991).

    Article  CAS  PubMed  Google Scholar 

  93. Badalamente, M. A. & Stracher, A. Delay of muscle degeneration and necrosis in mdx mice by calpain inhibition. Muscle Nerve 23, 106–111 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Spencer, M. J. & Mellgren, R. L. Overexpression of a calpastatin transgene in mdx muscle reduces dystrophic pathology. Hum. Mol. Genet. 11, 2645–2655 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Wrogemann, K. & Pena, S. D. Mitochondrial calcium overload: A general mechanism for cell-necrosis in muscle diseases. Lancet 1, 672–674 (1976).

    Article  CAS  PubMed  Google Scholar 

  96. Arahata, K. & Engel, A. G. Monoclonal antibody analysis of mononuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann. Neurol. 16, 193–208 (1984).

    Article  CAS  PubMed  Google Scholar 

  97. Engel, A. G. & Arahata, K. Monoclonal antibody analysis of mononuclear cells in myopathies. II: Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann. Neurol. 16, 209–215 (1984).

    Article  CAS  PubMed  Google Scholar 

  98. Arahata, K. & Engel, A. G. Monoclonal antibody analysis of mononuclear cells in myopathies. III: Immunoelectron microscopy aspects of cell-mediated muscle fiber injury. Ann. Neurol. 19, 112–125 (1986). References 96–98 suggest a role for cellular immunity in DMD.

    Article  CAS  PubMed  Google Scholar 

  99. Gorospe, J., Tharp, M. D., Hinckley, J., Kornegay, J. N. & Hoffman, E. P. A role for mast cells in the progression of Duchenne muscular dystrophy? Correlations in dystrophin-deficient humans, dogs, and mice. J. Neurol. Sci. 122, 44–56 (1994).

    Article  CAS  PubMed  Google Scholar 

  100. Chen, Y. -W., Zhao, P., Borup, R. & Hoffman, E. P. Expression profiling in the muscular dystrophies: Identification of novel aspects of molecular pathophysiology. J. Cell. Biol. 151, 1321–1326 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Haslett, J. N. et al. Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle. Proc. Natl Acad. Sci. USA 99, 15000–15005 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. D'Amore, P. A. et al. Elevated basic fibroblast growth factor in the serum of patients with Duchenne muscular dystrophy. Ann. Neurol. 35, 362–365 (1994).

    Article  CAS  PubMed  Google Scholar 

  103. Spencer, M. J., Montecino-Rodriguez, E., Dorshkind, K. & Tidball, J. G. Helper (CD4+) and cytotoxic (CD8+) T cells promote the pathology of dystrophin-deficient muscle. Clin. Immunol. 98, 235–243 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Granchelli, J. A., Pollina, C. & Hudecki, M. S. Duchenne-like myopathy in double-mutant mdx mice expressing exaggerated mast cell activity. J. Neurol. Sci. 131, 1–7 (1995).

    Article  CAS  PubMed  Google Scholar 

  105. Granchelli, J. A., Avosso, D. L., Hudecki, M. S. & Pollina, C. Cromolyn increases strength in exercised mdx mice. Res. Commun. Mol. Pathol. Pharmacol. 91, 287–296 (1996).

    CAS  PubMed  Google Scholar 

  106. Zeman, R. J., Zhang, Y. & Etlinger, J. D. Clenbuterol, a β2-agonist, retards wasting and loss of contractility in irradiated dystrophic mdx muscle. Am. J. Physiol. 267, C865–C868 (1994).

    Article  CAS  PubMed  Google Scholar 

  107. Pulido, S. M. et al. Creatine supplementation improves intracellular Ca2+ handling and survival in mdx skeletal muscle cells. FEBS Lett. 439, 357–362 (1998).

    Article  CAS  PubMed  Google Scholar 

  108. Walter, M. C. et al. Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study. Neurology 54, 1848–1850 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Barton-Davis, E. R., Cordier, L., Shoturma, D. I., Leland, S. E. & Sweeney, H. L. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J. Clin. Invest. 104, 375–381 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wagner, K. R. et al. Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations. Ann. Neurol. 49, 706–711 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Barton, E. R., Morris, L., Musaro, A., Rosenthal, N. & Sweeney, H. L. Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice. J. Cell. Biol. 157, 137–148 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gregorevic, P., Plant, D. R., Leeding, K. S., Bach, L. A. & Lynch, G. S. Improved contractile function of the mdx dystrophic mouse diaphragm muscle after insulin-like growth factor-I administration. Am. J. Pathol. 161, 2263–2272 (2002). References 111–112 demonstrate increasing muscle mass as a therapeutic strategy in DMD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. De Luca, A. et al. Enhanced dystrophic progression in mdx mice by exercise and beneficial effects of taurine and insulin-like growth factor-1. J. Pharmacol. Exp. Ther. 304, 453–463 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Charlier, C. et al. The mh gene causing double-muscling in cattle maps to bovine chromosome 2. Mamm. Genome 6, 788–792 (1995).

    Article  CAS  PubMed  Google Scholar 

  115. Grobet, L. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nature Genet. 1, 71–74 (1997).

    Article  Google Scholar 

  116. McPherron, A. C., Lawler, A. M. & Lee, S. J. Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member. Nature 387, 83–90 (1997). References 115 and 116 identify myostatin as a potent regulator of muscle progenitor cells.

    Article  CAS  PubMed  Google Scholar 

  117. Nishi, M. et al. A missense mutant myostatin causes hyperplasia without hypertrophy in the mouse muscle. Biochem. Biophys. Res. Commun. 293, 247–251 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Zhu, X., Hadhazy, M., Wehling, M., Tidball, J. G. & McNally, E. M. Dominant negative myostatin produces hypertrophy without hyperplasia in muscle. FEBS Lett. 474, 71–75 (2000).

    Article  CAS  PubMed  Google Scholar 

  119. Thies, R. S. et al. GDF-8 propeptide binds to GDF-8 and antagonizes biological activity by inhibiting GDF-8 receptor binding. Growth Factors 18, 251–259 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Lee, S. J. Regulation of myostatin activity and muscle growth. Proc. Natl Acad. Sci. USA 98, 9306–9311 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Thomas, M. et al. Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation. J. Biol. Chem. 275, 40235–40243 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Spiller, M. P. et al. The myostatin gene is a downstream target gene of basic helix-loop-helix transcription factor MyoD. Mol. Cell Biol. 22, 7066–7082 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Langley, B. et al. Myostatin inhibits myoblast differentiation by down-regulating MyoD expression. J. Biol. Chem. 277, 49831–49840 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Bogdanovich, S. et al. Functional improvement of dystrophic muscle by myostatin blockade. Nature 420, 418–421 (2002). Reference 124 demonstrates myostatin blockade as a pharmacological strategy in DMD.

    Article  CAS  PubMed  Google Scholar 

  125. Wagner, K. R., McPherron, A. C., Winik, N. & Lee, S. J. Loss of myostatin attenuates severity of muscular dystrophy in mdx mice. Ann. Neurol. 52, 832–836 (2002).

    Article  CAS  PubMed  Google Scholar 

  126. Escolar, D. M., Henricson, E. K., Pasquali, L., Gorni, K. & Hoffman, E. P. Collaborative translational research leading to multicenter clinical trials in Duchenne muscular dystrophy: the Cooperative International Neuromuscular Research Group (CINRG). Neuromuscul. Disord. 12, S147–S154 (2002).

    Article  PubMed  Google Scholar 

  127. Granchelli, J. A., Pollina, C. & Hudecki, M. S. Pre-clinical screening of drugs using the mdx mouse. Neuromuscul. Disord. 10, 235–239 (2000).

    Article  CAS  PubMed  Google Scholar 

  128. Ragot, T. et al. Efficient adenovirus-mediated transfer of a human minidystrophin gene to skeletal muscle of mdx mice. Nature 361, 647–650 (1993).

    Article  CAS  PubMed  Google Scholar 

  129. Mann, C. J. et al. Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse. Proc. Natl Acad. Sci. USA 98, 42–47 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. van Deutekom, J. C. et al. Antisense-induced exon skipping restores dystrophin expression in DMD patient derived muscle cells. Hum. Mol. Genet. 10, 1547–1554 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Bartlett, R. J. et al. In vivo targeted repair of a point mutation in the canine dystrophin gene by a chimeric RNA/DNA oligonucleotide. Nature Biotechnol. 18, 615–622 (2000).

    Article  CAS  Google Scholar 

  132. Rando, T. A., Disatnik, M. H. & Zhou, L. Z. Rescue of dystrophin expression in mdx mouse muscle by RNA/DNA oligonucleotides. Proc. Natl Acad. Sci. USA 97, 5363–5368 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Partridge, T. A., Morgan, J. E., Coulton, G. R., Hoffman, E. P. & Kunkel, L. M. Conversion of mdx myofibres from dystrophin-negative to -positive by injection of normal myoblasts. Nature 337, 176–179 (1989).

    Article  CAS  PubMed  Google Scholar 

  134. Bittner, R. E. et al. Recruitment of bone-marrow-derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice. Anat. Embryol. (Berl.) 199, 391–396 (1999).

    Article  CAS  Google Scholar 

  135. Gussoni, E. et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401, 390–394 (1999). References 128–135 describe a variety of gene and cell-based therapies for DMD.

    CAS  PubMed  Google Scholar 

  136. Sgouras, D. N. et al. ERF: an ets domain protein with strong transcriptional repressor activity, can suppress ets–associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation. EMBO J. 14, 4781–4793 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We dedicate this article to the memory of our colleague K. Arahata, whose tireless efforts and scholarship serve as an inspiration in the quest for a cure. We are indebted to the patients, families and organizations who have donated the samples and provided the funding that makes our research possible. Supported by grants from The Medical Research Council (UK), The Muscular Dystrophy Group (UK), Association Contre les Myopathies (France), Duchenne Parents Project (The Netherlands), The Muscular Dystrophy Association (USA) and the National Institutes of Health (USA). We are grateful to S. Bogdanovich, T. Krag and K. Perkins for contributing illustrations and tables. We thank them, as well as numerous other colleagues, for insightful suggestions.

Author information

Authors and Affiliations

  1. Department of Physiology & Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104-6085, PA, USA

    Tejvir S. Khurana

  2. Department of Human Anatomy and Genetics, MRC Functional Genetics Unit, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK

    Kay E. Davies

Authors
  1. Tejvir S. Khurana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kay E. Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tejvir S. Khurana.

Related links

Related links

DATABASES

LocusLink

DMD

DRP2

dystrobrevin

dystroglycan

myostatin

utrophin

Online Mendelian Inheritance in Man

Becker muscular dystrophy

Duchenne muscular dystrophy

FURTHER INFORMATION

Encyclopedia of Life Sciences

Duchenne muscular dystrophy

Leiden Muscular Dystrophy Pages

Cooperative Neuromuscular Research Group

Glossary

DUCHENNE MUSCULAR DYSTROPHY

(DMD) A common, genetic neuromuscular disease associated with progressive deterioration of muscle function. In about a third of cases DMD is also associated with impairment of cognitive ability.

DYSTROPHIN-RELATED PROTEINS

A family of proteins that are structurally and functionally related to dystrophin, consisting of utrophin or DRP, DRP2 and dystrobrevin. Utrophin seems capable of functionally substituting for the missing dystrophin and improving muscle pathology when experimentally overexpressed.

SARCOLEMMA

A thin membrane enclosing a striated muscle fibre.

REGENERATION

Muscle has limited ability to regenerate and repair itself when damaged. Cells contained within mature muscle known as satellite cells (sometimes referred to as committed stem cells), proliferate in response to damage and attempt to repair it.

NECROSIS

The death of a cell due to external damage or the action of toxic substances. Distinct from programmed cell death (apoptosis), which is a normal part of the developmental process.

ECCENTRIC CONTRACTION

Skeletal muscle usually contracts when stimulated. Lengthening of muscle during an active contraction is known as an eccentric contraction (ECC). Dystrophic muscle is particularly susceptible to damage during ECC.

PROMOTER

A region of a gene that controls expression of that gene. Its activity is controlled by transcription factors that in turn are activated or repressed by a number of extra- and intracellular mechanisms.

MYOGENIC

Originating in or produced by muscle cells.

MYOBLAST

An undifferentiated cell in the mesoderm of the vertebrate embryo that is a precursor of a muscle cell.

CALCIUM HOMEOSTASIS

The ability of a cell to maintain the requisite intracellular calcium concentration. The body and individual cells have homeostatic mechanisms that can compensate or buffer the lowering or excess levels of intracellular calcium to some degree.

SARCOPLASMIC RETICULUM

A meshwork of internal membranes in muscle cells or fibres.

MYOTUBE

A muscle fibre precursor formed by the fusion of myoblasts.

LUCIFERASE

The enzyme that catalyses the oxidation of luciferin, a reaction that produces bioluminescence.

INCREASING MUSCLE MASS

Muscle mass can increase in response to a variety of physiological and pathological stimuli. Growth/developmental factors regulate muscle mass by complex mechanisms including regulation of the proliferation and differentiation of muscle precursor cells.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Khurana, T., Davies, K. Pharmacological strategies for muscular dystrophy. Nat Rev Drug Discov 2, 379–390 (2003). https://doi.org/10.1038/nrd1085

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1085

This article is cited by

Search

Advanced 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