Original Article

Enhanced Expression of the 7ß1 Integrin Reduces Muscular Dystrophy and Restores Viability in Dystrophic Mice

Correspondence to: Stephen J. Kaufman, Department of Cell and Structural Biology, University of Illinois, B107 Chemical and Life Sciences Laboratory, Urbana, IL 61801. Tel:(217) 333-3521 Fax:(217) 244-1648 E-mail:stephenk{at}uiuc.edu.

Muscle fibers attach to laminin in the basal lamina using two distinct mechanisms: the dystrophin glycoprotein complex and the 7ß1 integrin. Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), 2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and 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 7ß1 integrin can compensate for the absence of dystrophin, we expressed the rat 7 chain in mdx/utr^-/- 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 7BX2 integrin chain was increased 2.0–2.3-fold in mdx/utr^-/- mice. Concomitant with the increase in the 7 chain, its heterodimeric partner, ß1D, was also increased in the transgenic animals. Transgenic expression of the 7BX2 chain in the mdx/utr^-/- 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 7ß1 integrin–mediated association of muscle cells with the extracellular matrix alleviates many of the symptoms of disease observed in mdx/utr^-/- mice and compensates for the absence of the dystrophin- and utrophin-mediated linkage systems. This suggests that enhanced expression of the 7ß1 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^-/- and 7BX2-mdx/utr^-/- mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207.

Key Words: 7ß1 integrin, muscular dystrophy, dystrophin, utrophin, neuromuscular junction

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