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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.

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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).

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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.

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  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

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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

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