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 mechanisms: the dystrophin glycoprotein complex and the [Alpha]7[Beta]1 integrin. Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), [Alpha]2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and [Alpha]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 [Alpha]7[Beta]1 integrin can compensate for the absence of dystrophin, we expressed the rat [Alpha]7 chain in mdx/[utr.sup.-/-] 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 [Alpha]7BX2 integrin chain was increased 2.0-2.3-fold in mdx/[utr.sup.-/-] mice. Concomitant with the increase in the [Alpha]7 chain, its heterodimeric partner, [Beta]1D, was also increased in the transgenic animals. Transgenic expression of the [Alpha]BX2 chain in the mdx/[utr.sup.-/-] 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 [Alpha]7[Beta]1 integrin--mediated association of muscle cells with the extracellular matrix alleviates many of the symptoms of disease observed in mdx/[utr.sup.-/-] mice and compensates for the absence of the dystrophin- and utrophin-mediated linkage systems. This suggests that enhanced expression of the [Alpha]7[Beta]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.sup.-/-] and [Alpha]7BX2-mdx/[utr.sup.-/-] mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207. Key words: [Alpha]7[Beta]1 integrin * muscular dystrophy * dystrophin * utrophin * neuromuscular junction