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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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Expression of the rat α7 protein in mouse muscle. Immunofluorescence analysis of hindlimb cryosections using monoclonal antibodies against the rat α7 integrin chain, dystrophin, and utrophin. AChRs were stained with rhodamine-labeled α-bungarotoxin to identify NMJs, the sites of normal utrophin localization. The rat α7 protein is only detected in transgenic mice and localizes to the membrane of muscle fibers. The lack of dystrophin and utrophin in both transgenic and nontransgenic mdx/utr−/− mice confirms their genotypes. The fluorescent specks seen in the mdx/utr−/− muscle stained with mouse antidystrophin, antiutrophin, and anti-α7 integrin antibodies are also evident in the absence of primary antibody and are due to residual staining with secondary anti–mouse antibody.
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Figure 2: Expression of the rat α7 protein in mouse muscle. Immunofluorescence analysis of hindlimb cryosections using monoclonal antibodies against the rat α7 integrin chain, dystrophin, and utrophin. AChRs were stained with rhodamine-labeled α-bungarotoxin to identify NMJs, the sites of normal utrophin localization. The rat α7 protein is only detected in transgenic mice and localizes to the membrane of muscle fibers. The lack of dystrophin and utrophin in both transgenic and nontransgenic mdx/utr−/− mice confirms their genotypes. The fluorescent specks seen in the mdx/utr−/− muscle stained with mouse antidystrophin, antiutrophin, and anti-α7 integrin antibodies are also evident in the absence of primary antibody and are due to residual staining with secondary anti–mouse antibody.

Mentions: Protein expression from the rat α7 chain transgene was determined by immunofluorescence analysis of cryosections using the rat-specific α7 monoclonal antibody O26 (Fig. 2). The rat α7 chain was only detected by immunofluorescence in the muscle of transgenic mice (Fig. 2). Immunofluorescence also showed the absence of dystrophin in muscle fibers and the absence of utrophin at NMJs in both transgenic and nontransgenic mdx/utr−/− mice (Fig. 2). The fluorescent specks seen in Fig. 2 upon staining mdx/utr−/− muscle with mouse antidystrophin, antiutrophin, and anti-α7 integrin antibodies are visible in the absence of primary antibody and are due to residual staining with secondary anti–mouse antibody.


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)

Expression of the rat α7 protein in mouse muscle. Immunofluorescence analysis of hindlimb cryosections using monoclonal antibodies against the rat α7 integrin chain, dystrophin, and utrophin. AChRs were stained with rhodamine-labeled α-bungarotoxin to identify NMJs, the sites of normal utrophin localization. The rat α7 protein is only detected in transgenic mice and localizes to the membrane of muscle fibers. The lack of dystrophin and utrophin in both transgenic and nontransgenic mdx/utr−/− mice confirms their genotypes. The fluorescent specks seen in the mdx/utr−/− muscle stained with mouse antidystrophin, antiutrophin, and anti-α7 integrin antibodies are also evident in the absence of primary antibody and are due to residual staining with secondary anti–mouse antibody.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Expression of the rat α7 protein in mouse muscle. Immunofluorescence analysis of hindlimb cryosections using monoclonal antibodies against the rat α7 integrin chain, dystrophin, and utrophin. AChRs were stained with rhodamine-labeled α-bungarotoxin to identify NMJs, the sites of normal utrophin localization. The rat α7 protein is only detected in transgenic mice and localizes to the membrane of muscle fibers. The lack of dystrophin and utrophin in both transgenic and nontransgenic mdx/utr−/− mice confirms their genotypes. The fluorescent specks seen in the mdx/utr−/− muscle stained with mouse antidystrophin, antiutrophin, and anti-α7 integrin antibodies are also evident in the absence of primary antibody and are due to residual staining with secondary anti–mouse antibody.
Mentions: Protein expression from the rat α7 chain transgene was determined by immunofluorescence analysis of cryosections using the rat-specific α7 monoclonal antibody O26 (Fig. 2). The rat α7 chain was only detected by immunofluorescence in the muscle of transgenic mice (Fig. 2). Immunofluorescence also showed the absence of dystrophin in muscle fibers and the absence of utrophin at NMJs in both transgenic and nontransgenic mdx/utr−/− mice (Fig. 2). The fluorescent specks seen in Fig. 2 upon staining mdx/utr−/− muscle with mouse antidystrophin, antiutrophin, and anti-α7 integrin antibodies are visible in the absence of primary antibody and are due to residual staining with secondary anti–mouse antibody.

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