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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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Kaplan-Meier survival curves of 43 α7BX2-mdx/utr−/− and 84 mdx/utr−/− mice. Wilcoxon and log-rank tests show that the α7BX2-mdx/utr−/− and mdx/utr−/− mice populations have distinct survival curves (P < 0.001). The α7BX2-mdx/utr−/− mice survive threefold longer than nontransgenic mdx/utr−/− mice with a median life expectancy of 38 wk. In contrast, nontransgenic mdx/utr−/− mice have a median life expectancy of 12 wk (95% confidence intervals are indicated by shading).
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Figure 5: Kaplan-Meier survival curves of 43 α7BX2-mdx/utr−/− and 84 mdx/utr−/− mice. Wilcoxon and log-rank tests show that the α7BX2-mdx/utr−/− and mdx/utr−/− mice populations have distinct survival curves (P < 0.001). The α7BX2-mdx/utr−/− mice survive threefold longer than nontransgenic mdx/utr−/− mice with a median life expectancy of 38 wk. In contrast, nontransgenic mdx/utr−/− mice have a median life expectancy of 12 wk (95% confidence intervals are indicated by shading).

Mentions: Longevity was significantly extended in the α7BX2-mdx/utr−/− transgenic mice (Fig. 5). Kaplan-Meier survival analysis (Kaplan and Meier 1958) of 84 nontransgenic and 43 transgenic mdx/utr−/− mice demonstrated that the observed differences in survival of these populations were statistically significant (P < 0.001). Log-rank (Peto et al. 1977) and Wilcoxon rank-sum tests (Conover 1980) showed that the difference in survival emerged soon after birth and was maintained throughout the observed lifetime of the animals. The mdx/utr−/− mice used in these experiments developed severe muscular dystrophy and 50% died before 12 wk of age. The median age at death of the transgenic mdx/utr−/− mice was 38 wk, a threefold increase over that observed in nontransgenic mdx/utr−/− littermates. These findings were consistent in both male and female mice. The oldest α7BX2-mdx/utr−/− mouse was killed at 64 wk of age.


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)

Kaplan-Meier survival curves of 43 α7BX2-mdx/utr−/− and 84 mdx/utr−/− mice. Wilcoxon and log-rank tests show that the α7BX2-mdx/utr−/− and mdx/utr−/− mice populations have distinct survival curves (P < 0.001). The α7BX2-mdx/utr−/− mice survive threefold longer than nontransgenic mdx/utr−/− mice with a median life expectancy of 38 wk. In contrast, nontransgenic mdx/utr−/− mice have a median life expectancy of 12 wk (95% confidence intervals are indicated by shading).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 5: Kaplan-Meier survival curves of 43 α7BX2-mdx/utr−/− and 84 mdx/utr−/− mice. Wilcoxon and log-rank tests show that the α7BX2-mdx/utr−/− and mdx/utr−/− mice populations have distinct survival curves (P < 0.001). The α7BX2-mdx/utr−/− mice survive threefold longer than nontransgenic mdx/utr−/− mice with a median life expectancy of 38 wk. In contrast, nontransgenic mdx/utr−/− mice have a median life expectancy of 12 wk (95% confidence intervals are indicated by shading).
Mentions: Longevity was significantly extended in the α7BX2-mdx/utr−/− transgenic mice (Fig. 5). Kaplan-Meier survival analysis (Kaplan and Meier 1958) of 84 nontransgenic and 43 transgenic mdx/utr−/− mice demonstrated that the observed differences in survival of these populations were statistically significant (P < 0.001). Log-rank (Peto et al. 1977) and Wilcoxon rank-sum tests (Conover 1980) showed that the difference in survival emerged soon after birth and was maintained throughout the observed lifetime of the animals. The mdx/utr−/− mice used in these experiments developed severe muscular dystrophy and 50% died before 12 wk of age. The median age at death of the transgenic mdx/utr−/− mice was 38 wk, a threefold increase over that observed in nontransgenic mdx/utr−/− littermates. These findings were consistent in both male and female mice. The oldest α7BX2-mdx/utr−/− mouse was killed at 64 wk of age.

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