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

Burkin DJ, Wallace GQ, Nicol KJ, Kaufman DJ, Kaufman SJ - J. Cell Biol. (2001)

Bottom Line: Therefore, the molecular continuity between the extracellular matrix and cell cytoskeleton is essential for the structural and functional integrity of skeletal muscle.Concomitant with the increase in the alpha 7 chain, its heterodimeric partner, beta 1D, was also increased in the transgenic animals.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Structural Biology, University of Illinois, Urbana, Illinois 61801, USA.

ABSTRACT
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(-/-) 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(-/-) 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 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 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(-/-) 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(-/-) and alpha 7BX2-mdx/utr(-/-) mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207.

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X-ray and MRI of normal and dystrophic mice. Top three panels, the severe spinal curvature (kyphosis) and constriction of the rib cage in mdx/utr−/− mice are largely reduced in the α7BX2 transgenic animals; bottom four panels, MRI of midsagittal sections reveals that kyphosis and reduction of pulmonary volume in mdx/utr−/− mice are largely alleviated in transgenic mice.
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Figure 8: X-ray and MRI of normal and dystrophic mice. Top three panels, the severe spinal curvature (kyphosis) and constriction of the rib cage in mdx/utr−/− mice are largely reduced in the α7BX2 transgenic animals; bottom four panels, MRI of midsagittal sections reveals that kyphosis and reduction of pulmonary volume in mdx/utr−/− mice are largely alleviated in transgenic mice.

Mentions: Severe curvature of the spine (kyphosis) in DMD patients and mdx/utr−/− mice is due to a failure of the muscles that would normally support the spinal column (Oda et al. 1993). X-ray images showed that both kyphosis and rib cage compression were markedly reduced in α7BX2-mdx/utr−/− mice compared with mdx/utr−/− littermates (Fig. 8). This was confirmed by whole body MRI which visualized not only the tissues surrounding the spinal column, but bundles of muscle fibers, the heart, lung, and other soft tissues. The reduction in kyphosis promoted by the enhanced expression of integrin in the α7BX2-mdx/utr−/− animals is likely a major factor in their survival. Kyphosis results in the diaphragm being pushed forward, compromising lung capacity and diaphragm function, and thereby contributing to cardiopulmonary failure. A partial reduction of kyphosis may therefore have dramatic effects on survival.


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

Burkin DJ, Wallace GQ, Nicol KJ, Kaufman DJ, Kaufman SJ - J. Cell Biol. (2001)

X-ray and MRI of normal and dystrophic mice. Top three panels, the severe spinal curvature (kyphosis) and constriction of the rib cage in mdx/utr−/− mice are largely reduced in the α7BX2 transgenic animals; bottom four panels, MRI of midsagittal sections reveals that kyphosis and reduction of pulmonary volume in mdx/utr−/− mice are largely alleviated in transgenic mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199213&req=5

Figure 8: X-ray and MRI of normal and dystrophic mice. Top three panels, the severe spinal curvature (kyphosis) and constriction of the rib cage in mdx/utr−/− mice are largely reduced in the α7BX2 transgenic animals; bottom four panels, MRI of midsagittal sections reveals that kyphosis and reduction of pulmonary volume in mdx/utr−/− mice are largely alleviated in transgenic mice.
Mentions: Severe curvature of the spine (kyphosis) in DMD patients and mdx/utr−/− mice is due to a failure of the muscles that would normally support the spinal column (Oda et al. 1993). X-ray images showed that both kyphosis and rib cage compression were markedly reduced in α7BX2-mdx/utr−/− mice compared with mdx/utr−/− littermates (Fig. 8). This was confirmed by whole body MRI which visualized not only the tissues surrounding the spinal column, but bundles of muscle fibers, the heart, lung, and other soft tissues. The reduction in kyphosis promoted by the enhanced expression of integrin in the α7BX2-mdx/utr−/− animals is likely a major factor in their survival. Kyphosis results in the diaphragm being pushed forward, compromising lung capacity and diaphragm function, and thereby contributing to cardiopulmonary failure. A partial reduction of kyphosis may therefore have dramatic effects on survival.

Bottom Line: Therefore, the molecular continuity between the extracellular matrix and cell cytoskeleton is essential for the structural and functional integrity of skeletal muscle.Concomitant with the increase in the alpha 7 chain, its heterodimeric partner, beta 1D, was also increased in the transgenic animals.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Structural Biology, University of Illinois, Urbana, Illinois 61801, USA.

ABSTRACT
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(-/-) 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(-/-) 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 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 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(-/-) 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(-/-) and alpha 7BX2-mdx/utr(-/-) mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207.

Show MeSH
Related in: MedlinePlus