Enhanced expression of the α7β1 integrin reduces muscular dystrophy and restores viability in dystrophic mice

DJ Burkin, GQ Wallace, KJ Nicol, DJ Kaufman… - The Journal of cell …, 2001 - rupress.org
DJ Burkin, GQ Wallace, KJ Nicol, DJ Kaufman, SJ Kaufman
The Journal of cell biology, 2001rupress.org
Muscle fibers attach to laminin in the basal lamina using two distinct mechanisms: the
dystrophin glycoprotein complex and the α7β1 integrin. Defects in these linkage systems
result in Duchenne muscular dystrophy (DMD), α2 laminin congenital muscular dystrophy,
sarcoglycan-related muscular dystrophy, and α7 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 …
Muscle fibers attach to laminin in the basal lamina using two distinct mechanisms: the dystrophin glycoprotein complex and the α7β1 integrin. Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), α2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and α7 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 α7β1 integrin can compensate for the absence of dystrophin, we expressed the rat α7 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 α7BX2 integrin chain was increased 2.0–2.3-fold in mdx/utr−/− mice. Concomitant with the increase in the α7 chain, its heterodimeric partner, β1D, was also increased in the transgenic animals. Transgenic expression of the α7BX2 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 α7β1 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 α7β1 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 α7BX2-mdx/utr−/−mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207.
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