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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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Weight gain versus survival in five representative mdx/utr−/− mice and α7BX2-mdx/utr−/− mice. The majority of nontransgenic mdx/utr−/− mice undergo a crisis at 5–10 wk of age that results in a sudden loss of weight and premature death. Most transgenic mdx/utr−/− mice live longer and maintain weight. Eventually these too will go through a crisis that results in weight loss. The mean life span of the mdx/utr−/− mice illustrated here is 10.4 wk; the mean life span of the α7BX2-mdx/utr−/− mice illustrated here is 41.8 wk.
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Figure 6: Weight gain versus survival in five representative mdx/utr−/− mice and α7BX2-mdx/utr−/− mice. The majority of nontransgenic mdx/utr−/− mice undergo a crisis at 5–10 wk of age that results in a sudden loss of weight and premature death. Most transgenic mdx/utr−/− mice live longer and maintain weight. Eventually these too will go through a crisis that results in weight loss. The mean life span of the mdx/utr−/− mice illustrated here is 10.4 wk; the mean life span of the α7BX2-mdx/utr−/− mice illustrated here is 41.8 wk.

Mentions: Compared with mdx mice that exhibit minimal pathology, mdx/utr−/− mice do not maintain weight. Instead, these mice undergo a crisis period that results in weight loss and premature death at 4–20 wk of age (Deconinck et al. 1997b; Grady et al. 1997b). In contrast, α7BX2-mdx/utr−/− transgenic mice did not show sudden weight loss. Animal weight stabilized between 20 and 25 g (Fig. 6). No significant differences were found in the weights of mdx mice compared with α7BX2-mdx mice 3–30 wk of age. Thus, extra α7BX2 chain itself does not promote weight gain.


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)

Weight gain versus survival in five representative mdx/utr−/− mice and α7BX2-mdx/utr−/− mice. The majority of nontransgenic mdx/utr−/− mice undergo a crisis at 5–10 wk of age that results in a sudden loss of weight and premature death. Most transgenic mdx/utr−/− mice live longer and maintain weight. Eventually these too will go through a crisis that results in weight loss. The mean life span of the mdx/utr−/− mice illustrated here is 10.4 wk; the mean life span of the α7BX2-mdx/utr−/− mice illustrated here is 41.8 wk.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 6: Weight gain versus survival in five representative mdx/utr−/− mice and α7BX2-mdx/utr−/− mice. The majority of nontransgenic mdx/utr−/− mice undergo a crisis at 5–10 wk of age that results in a sudden loss of weight and premature death. Most transgenic mdx/utr−/− mice live longer and maintain weight. Eventually these too will go through a crisis that results in weight loss. The mean life span of the mdx/utr−/− mice illustrated here is 10.4 wk; the mean life span of the α7BX2-mdx/utr−/− mice illustrated here is 41.8 wk.
Mentions: Compared with mdx mice that exhibit minimal pathology, mdx/utr−/− mice do not maintain weight. Instead, these mice undergo a crisis period that results in weight loss and premature death at 4–20 wk of age (Deconinck et al. 1997b; Grady et al. 1997b). In contrast, α7BX2-mdx/utr−/− transgenic mice did not show sudden weight loss. Animal weight stabilized between 20 and 25 g (Fig. 6). No significant differences were found in the weights of mdx mice compared with α7BX2-mdx mice 3–30 wk of age. Thus, extra α7BX2 chain itself does not promote weight gain.

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