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Human Molecular Genetics Advance Access published online on February 13, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl018
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© The Author 2006. Published by Oxford University Press. All rights reserved The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oupjournals.org
Received September 12, 2005
Revised February 2, 2006
Accepted February 2, 2006

Article

Absence of {alpha}7 integrin in dystrophin-deficient mice causes a myopathy similar to Duchenne muscular dystrophy

Chun Guo 1, Michael Willem 2, Alexander Werner 3, Gennadij Raivich 3, Michael Emerson 4, Ludwig Neyses 5, and Ulrike Mayer 6 *

1 Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK
2 Department for Alzheimer's Research, Adolf-Butenandt-Institute, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
3 Department of Neuromorphology, Max-Planck Institute for Neurobiology, 82152 Martinsried, Germany
4 Division of Cardiology, University of Manchester, Manchester, M13 9PT, UK; Division of Biomedical Sciences, Imperial College London, London SW7 2AZ, UK
5 Division of Cardiology, University of Manchester, Manchester, M13 9PT, UK
6 Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK; School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, UK

* To whom correspondence should be addressed.
Ulrike Mayer, E-mail: u.mayer{at}uea.ac.uk


  Abstract

Both the dystrophin-glycoprotein complex and (7(1 integrin have critical roles in the maintenance of muscle integrity via the provision of mechanical links between muscle fibers and the basement membrane. Absence of either dystrophin or (7 integrin results in a muscular dystrophy. To clarify the role of (7 integrin and dystrophin in muscle development and function, we generated integrin {alpha}7/dystrophin double-mutant (DKO) mice. Surprisingly, DKO mice survived postnatally and were indistinguishable from wild-type, integrin {alpha}7-deficient and mdx mice at birth, but died within 24-28 days. Histological analysis revealed a severe muscular dystrophy in DKO mice with endomysial fibrosis and ectopic calcification. Weight loss was correlated to the loss of muscle fibers, indicating that progressive muscle wasting in the double mutant was most likely due to inadequate muscle regeneration. The data further support that premature death of DKO mice is due to cardiac and/or respiratory failure. The integrin {alpha}7/dystrophin-deficient mouse model therefore resembles the pathological changes seen in Duchenne muscular dystrophy (DMD), and suggests that the different clinical severity of dystrophin deficiency in human and mouse may be due to a fine-tuned difference in expression of dystrophin and integrin {alpha}7 in both species. Together, these findings indicate an essential role for integrin {alpha}7 in the maintenance of dystrophin-deficient muscles.


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