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Defective integrin switch and matrix composition at alpha 7- deficient myotendinous junctions precede the onset of muscular dystrophy in mice

MPG-Autoren
http://pubman.mpdl.mpg.de/cone/persons/resource/persons78884

Willem,  M.
Former Research Groups, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78376

Mayer,  U.
Former Research Groups, Max Planck Institute of Biochemistry, Max Planck Society;

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Zitation

Nawrotzki, R., Willem, M., Miosge, N., Brinkmeier, H., & Mayer, U. (2003). Defective integrin switch and matrix composition at alpha 7- deficient myotendinous junctions precede the onset of muscular dystrophy in mice. Human Molecular Genetics, 12(5), 483-495.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0010-6C83-7
Zusammenfassung
Force transmission at the myotendinous junction requires a strong link between the muscle cytoskeleton and the extracellular matrix. At the adult junction, two splice variants of the laminin-binding integrins, alpha7Abeta1D and alpha7Bbeta1D, are highly enriched. The alpha7 subunits are critical for the integrity of the junctional sarcolemma because integrin alpha7-deficient mice develop muscular dystrophy, primarily affecting this site of the muscle. Here, we report that beta1D integrin coimmunoprecipitates and colocalizes with the alpha5 subunit at alpha7-deficient junctions, but does not associate with alpha3, alpha6 or alphav integrins. By immunogold labelling we show that the basement membranes of integrin alpha7-deficient muscles recruit abnormally high levels of fibronectin, the ligand of alpha5beta1D. Finally, we demonstrate that alpha5beta1D is down-regulated at the normal postnatal junction and is displaced by alpha7beta1D. These results suggest that the alpha7 subunit is implicated in the down-regulation of alpha5beta1D and in the removal of fibronectin from the maturing myotendinous junction, thus providing an alpha7beta1D-based link to laminin. We propose that the persistence of alpha5beta1D in alpha7-deficient mice is not compatible with normal muscle function and leads to muscle wasting.