Enhanced expression of the alpha 7 beta 1 integrin reduces muscular dystrophy and restores viability in dystrophic mice

Muscle fibers attach to laminin in the basal lamina using two distinct mech anisms: the dystrophin glycoprotein complex and the alpha7 beta1 integrin, Defects in these linkage systems result in Duchenne muscular dystrophy (DMD ), alpha2 laminin congenital muscular dystrophy, sarcoglycan-related muscul ar dystrophy, and alpha7 integrin congenital muscular dystrophy. Therefore, the molecular continuity between the extracellular matrix and cell cytoske leton is essential for the structural and functional integrity of skeletal muscle. To test whether the alpha7 beta1 integrin can compensate for the ab sence of dystrophin, we expressed the rat alpha7 chain in mdx/utr(-/-) mice that lack both dystrophin and utrophin. These mice develop a severe muscul ar dystrophy highly akin to that in DMD, and they also die prematurely, Usi ng the muscle creatine kinase promoter, expression of the alpha 7BX2 integr in chain was increased 2.0-2.3-fold in mdx/utr(-/-) mice. Concomitant with the increase in the alpha7 chain, its heterodimeric partner, beta 1D was al so increased in the transgenic animals. Transgenic expression of the alpha 7BX2 chain in the mdx/utr(-/-) mice extended their longevity by threefold, reduced kyphosis and the development of muscle disease, and maintained mobi lity and the structure of the neuromuscular junction. Thus, bolstering alph a7 beta1 integrin-mediated association of muscle cells with the extracellul ar matrix alleviates many of the symptoms of disease observed in mdx/utr(-/ -) mice and compensates for the absence of the dystrophin- and utrophin-med iated linkage systems. This suggests that enhanced expression of the alpha7 beta1 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 m dx/utr(-/-) and alpha 7BX2-mdx/utr(-/-) mice can be accessed at http://www. jcb.org/cgi/content/full/152/6/1207.