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, α7Aβ1D and α7Bβ1D, are highly enriched. The α7 subunits are critical for the integrity of the junctional sarcolemma because integrin α7-deficient mice develop muscular dystrophy, primarily affecting this site of the muscle. Here, we report that β1D integrin coimmunoprecipitates and colocalizes with the α5 subunit at α7-deficient junctions, but does not associate with α3, α6 or αv integrins. By immunogold labelling we show that the basement membranes of integrin α7-deficient muscles recruit abnormally high levels of fibronectin, the ligand of α5β1D. Finally, we demonstrate that α5β1D is down-regulated at the normal postnatal junction and is displaced by α7β1D. These results suggest that the α7 subunit is implicated in the down-regulation of α5β1D and in the removal of fibronectin from the maturing myotendinous junction, thus providing an α7β1D-based link to laminin. We propose that the persistence of α5β1D in α7-deficient mice is not compatible with normal muscle function and leads to muscle wasting.