Integrin Reduces Muscular Dystrophy and Restores Viability in Dystrophic Mice

Muscle fibers attach to laminin in the basal lamina using two distinct mechanisms: the dystrophin glycoprotein complex and the a 7 b 1 integrin. Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), a 2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and a 7 integrin congenital muscular dystrophy. Therefore, the molecular continuity between the extracellular matrix and cell cytoskeleton is essential for the structural and functional integrity of skeletal muscle. To test whether the a 7 b 1 integrin can compensate for the absence of dystrophin, we expressed the rat a 7 chain in mdx/utr 2 / 2 mice that lack both dystrophin and utrophin. These mice develop a severe muscular dystrophy highly akin to that in DMD, and they also die prematurely. Using the muscle creatine kinase promoter, expression of the a 7BX2 integrin chain was increased 2.0–2.3-fold in mdx/utr 2 / 2 mice. Concomitant with the increase in the a 7 chain, its heterodimeric partner, b 1D, was also increased in the transgenic animals. Transgenic expression of the a 7BX2 chain in the mdx/utr 2 / 2 mice extended their longevity by threefold, reduced kyphosis and the development of muscle disease, and maintained mobility and the structure of the neuromuscular junction. Thus, bolstering a 7 b 1 integrin– mediated association of muscle cells with the extracellular matrix alleviates many of the symptoms of disease observed in mdx/utr 2 / 2 mice and compensates for the absence of the dystrophinand utrophin-mediated linkage systems. This suggests that enhanced expression of the a 7 b 1 integrin may provide a novel approach to treat DMD and other muscle diseases that arise due to defects in the dystrophin glycoprotein complex. A video that contrasts kyphosis, gait, joint contractures, and mobility in mdx/utr 2 / 2 and a 7BX2-mdx/utr 2 / 2 mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207.