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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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Immunofluores-cence of β1 integrin isoforms in the hindlimb of 8-wk-old wild-type, mdx, mdx/utr−/−, and α7BX2-mdx/utr−/− mice. β1A integrin is elevated in muscle fibers of mdx/utr−/− mice compared with wild-type and mdx animals. In contrast, β1A levels are normal in α7BX2-mdx/utr−/− mice. Compared with wild-type, an increase in β1D is detected in both mdx and mdx/utr−/− muscle. α7BX2-mdx/utr−/− mice show an additional increase in β1D compared with both mdx and mdx/utr−/− mice.
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Figure 3: Immunofluores-cence of β1 integrin isoforms in the hindlimb of 8-wk-old wild-type, mdx, mdx/utr−/−, and α7BX2-mdx/utr−/− mice. β1A integrin is elevated in muscle fibers of mdx/utr−/− mice compared with wild-type and mdx animals. In contrast, β1A levels are normal in α7BX2-mdx/utr−/− mice. Compared with wild-type, an increase in β1D is detected in both mdx and mdx/utr−/− muscle. α7BX2-mdx/utr−/− mice show an additional increase in β1D compared with both mdx and mdx/utr−/− mice.

Mentions: The alternative spliced form of the β1 integrin chain, β1D, is expressed in differentiated skeletal and cardiac muscle (van der Flier et al. 1995; Zhidkova et al. 1995; Belkin et al. 1996). Compared with the β1A, β1D may form stronger linkages between the cell cytoskeleton and extracellular matrix (Belkin et al. 1997). Immunofluorescence analysis showed β1A levels were elevated in fibers of mdx/utr−/− mice compared with wild-type and mdx animals. This is indicative of muscle that is not fully differentiated. In contrast, α7BX2-mdx/utr−/− mice had normal levels of β1A integrin. Immunofluorescence and Western blot analysis showed that mdx and mdx/utr−/− mice have more cell surface β1D chain than wild-type mice. This increase in β1D coincided with an increase in endogenous α7 chain in nontransgenic mdx and mdx/utr−/− mice as well as total α7 in α7BX2-mdx/utr−/− mice. The α7BX2-mdx/utr−/− mice also had an additional 1.5-fold more β1D compared with mdx/utr−/− mice (Fig. 3 and Fig. 4 C). Thus, an increase in the α7BX2β1D integrin is promoted by increased expression of the α7 transgene.


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)

Immunofluores-cence of β1 integrin isoforms in the hindlimb of 8-wk-old wild-type, mdx, mdx/utr−/−, and α7BX2-mdx/utr−/− mice. β1A integrin is elevated in muscle fibers of mdx/utr−/− mice compared with wild-type and mdx animals. In contrast, β1A levels are normal in α7BX2-mdx/utr−/− mice. Compared with wild-type, an increase in β1D is detected in both mdx and mdx/utr−/− muscle. α7BX2-mdx/utr−/− mice show an additional increase in β1D compared with both mdx and mdx/utr−/− mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2199213&req=5

Figure 3: Immunofluores-cence of β1 integrin isoforms in the hindlimb of 8-wk-old wild-type, mdx, mdx/utr−/−, and α7BX2-mdx/utr−/− mice. β1A integrin is elevated in muscle fibers of mdx/utr−/− mice compared with wild-type and mdx animals. In contrast, β1A levels are normal in α7BX2-mdx/utr−/− mice. Compared with wild-type, an increase in β1D is detected in both mdx and mdx/utr−/− muscle. α7BX2-mdx/utr−/− mice show an additional increase in β1D compared with both mdx and mdx/utr−/− mice.
Mentions: The alternative spliced form of the β1 integrin chain, β1D, is expressed in differentiated skeletal and cardiac muscle (van der Flier et al. 1995; Zhidkova et al. 1995; Belkin et al. 1996). Compared with the β1A, β1D may form stronger linkages between the cell cytoskeleton and extracellular matrix (Belkin et al. 1997). Immunofluorescence analysis showed β1A levels were elevated in fibers of mdx/utr−/− mice compared with wild-type and mdx animals. This is indicative of muscle that is not fully differentiated. In contrast, α7BX2-mdx/utr−/− mice had normal levels of β1A integrin. Immunofluorescence and Western blot analysis showed that mdx and mdx/utr−/− mice have more cell surface β1D chain than wild-type mice. This increase in β1D coincided with an increase in endogenous α7 chain in nontransgenic mdx and mdx/utr−/− mice as well as total α7 in α7BX2-mdx/utr−/− mice. The α7BX2-mdx/utr−/− mice also had an additional 1.5-fold more β1D compared with mdx/utr−/− mice (Fig. 3 and Fig. 4 C). Thus, an increase in the α7BX2β1D integrin is promoted by increased expression of the α7 transgene.

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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Related in: MedlinePlus