title: Defective integrin switch and matrix composition at alpha 7-deficient myotendinous junctions precede the onset of muscular dystrophy in mice.
abstract: 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.
authors.affiliation: Max-Planck-Institute for Biochemistry, 82152 Martinsried, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Nawrotzki
authors.forename: Michael
authors.initials: M
authors.lastname: Willem
authors.forename: Nicolai
authors.initials: N
authors.lastname: Miosge
authors.forename: Heinrich
authors.initials: H
authors.lastname: Brinkmeier
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mayer
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D016189:Dystrophin / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D007150:Immunohistochemistry; D016023:Integrins / Q000172:deficiency* / Q000502:physiology; D051379:Mice; D009132:Muscles / Q000503:physiopathology*; D009137:Muscular Dystrophy, Animal / Q000503:physiopathology*; D013710:Tendons / Q000503:physiopathology*
chemical_list: D016189:Dystrophin; D005353:Fibronectins; D016023:Integrins