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.

  • Article
  • Published:

Expression of full-length utrophin prevents muscular dystrophy in mdx mice

Nature Medicine volume 4, pages 1441–1444 (1998)Cite this article

Abstract

Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting disease caused by a loss of sarcolemmal bound dystrophin, which results in the death of the muscle fiber leading to the gradual depletion of skeletal muscle 1 . The molecular structure of dystrophin is very similar to that of the related protein utrophin 2 . Utrophin is found in all tissues 3 and is confined to the neuromuscular and myotendinous junctions in mature muscle 4 . Sarcolemmal localization of a truncated utrophin transgene in the dystrophin-deficient mdx mouse significantly improves the dystrophic muscle phenotype 5, 6 . Therefore, upregulation of utrophin by drug therapy is a plausible therapeutic approach in the treatment of DMD. Here we demonstrate that expression of full-length utrophin in mdx mice prevents the development of muscular dystrophy. We assessed muscle morphology, fiber regeneration and mechanical properties (force development and resistance to stretch) of mdx and transgenic mdx skeletal and diaphragm muscle. The utrophin levels required in muscle are significantly less than the normal endogenous utrophin levels seen in lung and kidney, and we provide evidence that the pathology depends on the amount of utrophin expression. These results also have important implications for DMD therapies in which utrophin replacement is achieved by delivery using exogenous vectors.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Utrophin transgene expression in the Fio, Fer and Fre lines.
Figure 2: Mechanics of isolated muscle.
Figure 3: Whole body tension (WBT) monitored in the 'escape' test.
Figure 4: Recovery scores obtained in muscles from the Utr++ lines (truncated utrophin; ▪) and the Fio (░) and Fre (▨) lines (full-length utrophpin).

Similar content being viewed by others

References

  1. Emery, A.E.H. in Duchenne Muscular Dystrophy (Oxford Medical Publications, Oxford, 1993).

    Google Scholar 

  2. Tinsley, J.M. et al. Primary structure of dystrophin-related protein. Nature 360, 591–593 (1992).

    Article  CAS  Google Scholar 

  3. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Deconinck, N. et al. Expression of truncated utrophin leads to major functional improvements in dystrophin-deficient muscles of mice. Nature Med. 3, 1216–1221 (1997).

    Article  CAS  Google Scholar 

  6. Tinsley, J.M. et al. Amelioration of the dystrophic phenotype of mdx mice using a truncated utrophin transgene. Nature 384, 349–353 (1996).

    Article  CAS  Google Scholar 

  7. Brennan, K.J. & Hardeman, E.C. Quantitative analysis of the human alpha-skeletal actin gene in transgenic mice. J. Biol. Chem. 268, 719–725 (1993).

    CAS  PubMed  Google Scholar 

  8. 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  Google Scholar 

  9. Blake, D.J. et al. G-utrophin, the autosomal homologue of dystrophin Dp116, is expressed in sensory ganglia and brain. Proc. Natl. Acad. Sc.i USA 92, 3697–3701 (1995).

    Article  CAS  Google Scholar 

  10. Straub, V. & Campbell, K.P. Muscular dystrophies and the dystrophin-glycoprotein complex. Curr. Opin. Neurol. 10, 168–175 (1997).

    Article  CAS  Google Scholar 

  11. Sadoulet, P.H., Rajala, M. & Kunkel, L.M. Dystrobrevin and dystrophin: an interaction through coiled-coil motifs. Proc. Natl. Acad. Sci. USA 94, 12413–12418 (1997).

    Article  Google Scholar 

  12. Suzuki, A., Yoshida, M. & Ozawa, E. Mammalian alpha 1- and beta 1-syntrophin bind to the alternative splice-prone region of the dystrophin COOH terminus. J. Cell. Biol. 128, 373–381 (1995).

    Article  CAS  Google Scholar 

  13. Blake, D.J., Nawrotzki, R., Loh, N.Y., Gorecki, D.C. & Davies, K.E. beta-dystrobrevin, a member of the dystrophin-related protein family. Proc. Natl. Acad. Sci. USA 95, 241–246 (1998).

    Article  CAS  Google Scholar 

  14. 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  Google Scholar 

  15. 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  CAS  Google Scholar 

  16. Weller, B., Karpati, G. & Carpenter, S. Dystrophin-deficient mdx muscle fibers are preferentially vulnerable to necrosis induced by experimental lengthening contractions. J. Neurol. Sci. 100, 9–13 (1990).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. 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  Google Scholar 

  19. Carlson, C.G. & Makiejus, R.V. A non-invassive procedure to detect muscle weakness in the mdx mouse. Muscle Nerve 13, 480–484 (1990).

    Article  CAS  Google Scholar 

  20. Deconinck, A.E. et al. Postsynaptic abnormalities at the neuromuscular junctions of utrophin-deficient mice. J. Cell. Biol. 136, 88–894 (1997).

    Article  Google Scholar 

Download references

Acknowledgements

We thank L. Townsend for technical assistance and D.J. Blake for the dystrobrevin antibody. We thank the Medical Research Council (UK), the Muscular Dystrophy Group of Great Britain and Northern Ireland, the Muscular Dystrophy Association of the USA, Association Francaise Contre les Myopathies and the Association Belge Contre les Maladies Neuromusculaires for financial support. N.D. is a research fellow of the Fonds National de la Recherche Scientifique of Belgium.

Author information

Authors and Affiliations

  1. Department of Human Anatomy and Genetics, South Parks Road, University of Oxford, Oxford, OX1 3QX, UK

    Jonathon Tinsley, Rosie Fisher, Steve Phelps & Kay Davies

  2. Départment de Physiologie, UCL 5540, Université Catholique de Louvain, Avenue Hippocrate 55, Brussels, 1200, Belgium

    Nicolas Deconinck, David Kahn & Jean-Marie Gillis

Authors
  1. Jonathon Tinsley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicolas Deconinck
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rosie Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Kahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steve Phelps
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jean-Marie Gillis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kay Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tinsley, J., Deconinck, N., Fisher, R. et al. Expression of full-length utrophin prevents muscular dystrophy in mdx mice. Nat Med 4, 1441–1444 (1998). https://doi.org/10.1038/4033

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/4033

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