Human Molecular Genetics, 2002, Vol. 11, No. 26 3333-3344
© 2002 Oxford University Press
Prevention of pathology in mdx mice by expression of utrophin: analysis using an inducible transgenic expression system
1MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK, and 2Department of Physiology, UCL 5540 Catholic University of Louvain, 55, av Hippocrate, 1200 Bruxelles, Belgium
Received August 30, 2002; Accepted October 28, 2002
Duchenne muscular dystrophy results from the absence of dystrophin, a cytoskeletal protein. Previously, we have shown in a transgenic mouse model of the disease (mdx) that high levels of expression of the dystrophin-related protein, utrophin can prevent pathology. We developed a new transgenic mouse model where muscle specific utrophin expression was conditioned by addition of tetracycline in water. Transgene expression was turned on at different time points: in utero, at birth, 10 and 30 days after birth. We obtained moderate levels of expression, variable from fibre to fibre (mosaicism) but sufficient to induce a correct localization of the dystro-sarcoglycan complex. Histology revealed a reduction of necrotic foci and of the percentage of centronucleated fibres, which remained still largely above the normal level. Isometric force was not improved but the resistance to eccentric contractions was significantly stronger. When utrophin expression was activated 30 days after birth, improvements were marginal, suggesting that the age at which utrophin therapy is initiated could be an important factor. Our results also provide an unexpected insight into the pathogenesis of the dystrophinopathies. We observed a complete normalization of the characteristics of the mechano-sensitive/voltage-independent Ca2+ channels (occurrence, open probabilities and Ca2+ currents), while the classical markers of dystrophy were still abnormal. These observations question the role of increased Ca2+ channel activity in initiating the dystrophic process. The new model shows that utrophin therapy, initiated after birth, can be effective, but the extent of correction of the various symptoms of dystrophinopathy critically depends on the amount of utrophin expressed.
* To whom correspondence should be addressed at: MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK. Tel: +44 1865272179; Fax: +44 1865272427; Email: kay.davies{at}anat.ox.ac.uk
Present address: Oxagen Ltd, 91 Milton Park, Abingdon, Oxon, OX14 4RY, UK.
The authors would like it to be known that, in their opinion, these three authors should be considered as joint First Authors.
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