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Animal models for muscular dystrophy show different patterns of sarcolemmal disruption.

Straub V, Rafael JA, Chamberlain JS, Campbell KP - J. Cell Biol. (1997)

Bottom Line: However, little is known about how alterations in the DGC are manifested in the pathophysiology present in dystrophic muscle tissue.One hypothesis is that the DGC protects the sarcolemma from contraction-induced damage.Taken together, these results suggest that the pathogenic mechanisms in congenital muscular dystrophy are different from those in Duchenne muscular dystrophy, although the primary defects originate in two components associated with the same protein complex.

View Article: PubMed Central - PubMed

Affiliation: Department of, Howard Hughes Medical Institute, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.

ABSTRACT
Genetic defects in a number of components of the dystrophin-glycoprotein complex (DGC) lead to distinct forms of muscular dystrophy. However, little is known about how alterations in the DGC are manifested in the pathophysiology present in dystrophic muscle tissue. One hypothesis is that the DGC protects the sarcolemma from contraction-induced damage. Using tracer molecules, we compared sarcolemmal integrity in animal models for muscular dystrophy and in muscular dystrophy patient samples. Evans blue, a low molecular weight diazo dye, does not cross into skeletal muscle fibers in normal mice. In contrast, mdx mice, a dystrophin-deficient animal model for Duchenne muscular dystrophy, showed significant Evans blue accumulation in skeletal muscle fibers. We also studied Evans blue dispersion in transgenic mice bearing different dystrophin mutations, and we demonstrated that cytoskeletal and sarcolemmal attachment of dystrophin might be a necessary requirement to prevent serious fiber damage. The extent of dye incorporation in transgenic mice correlated with the phenotypic severity of similar dystrophin mutations in humans. We furthermore assessed Evans blue incorporation in skeletal muscle of the dystrophia muscularis (dy/dy) mouse and its milder allelic variant, the dy2J/dy2J mouse, animal models for congenital muscular dystrophy. Surprisingly, these mice, which have defects in the laminin alpha2-chain, an extracellular ligand of the DGC, showed little Evans blue accumulation in their skeletal muscles. Taken together, these results suggest that the pathogenic mechanisms in congenital muscular dystrophy are different from those in Duchenne muscular dystrophy, although the primary defects originate in two components associated with the same protein complex.

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EBD staining on 7-μm cryosections of mdx cardiac  muscle. EBD-positive cardiomyocytes were detected in 8 out of  16 mdx mice but never in control animals. One intravenously injected 4-wk-old animal showed large areas of dye uptake into the  myocardium (a), whereas in other mice, smaller regions of EBD-positive fibers were found in the ventricular walls (b). Cardiac  dye uptake in intraperitoneally injected mdx mice (c, 10-mo-old  animal) demonstrated that the fiber damage was caused by the  underlying disease and not by a volume overload of intravenously  administered dye, leading to a cardiac infarct. Bars, 100 μm.
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Figure 3: EBD staining on 7-μm cryosections of mdx cardiac muscle. EBD-positive cardiomyocytes were detected in 8 out of 16 mdx mice but never in control animals. One intravenously injected 4-wk-old animal showed large areas of dye uptake into the myocardium (a), whereas in other mice, smaller regions of EBD-positive fibers were found in the ventricular walls (b). Cardiac dye uptake in intraperitoneally injected mdx mice (c, 10-mo-old animal) demonstrated that the fiber damage was caused by the underlying disease and not by a volume overload of intravenously administered dye, leading to a cardiac infarct. Bars, 100 μm.

Mentions: We also examined cardiac muscle from all injected animals, since cardiac involvement is a common feature in many forms of muscular dystrophy. Control mice never showed EBD-positive fibers in cardiac muscle tissue. In contrast, 8 out of 16 mdx mice had EBD-positive lesions in the myocardium. In one 4-wk-old mouse, large areas of the cardiac section showed EBD uptake into cardiac muscle fibers (Fig. 3 a), whereas in the other mice, ranging from 6 to 52 wk of age, regions of variable size in the ventricular wall were affected (Fig. 3, b and c). On sections stained with H&E, the EBD-positive areas showed characteristic features of myocardial damage, with a strong inflammatory component (data not shown). Myocardial EBD staining in intraperitoneally injected mice (Fig. 3 c) provided evidence that the fiber damage was caused by the underlying disease and not by volume overload of intravenously administered dye, leading to a cardiac infarct.


Animal models for muscular dystrophy show different patterns of sarcolemmal disruption.

Straub V, Rafael JA, Chamberlain JS, Campbell KP - J. Cell Biol. (1997)

EBD staining on 7-μm cryosections of mdx cardiac  muscle. EBD-positive cardiomyocytes were detected in 8 out of  16 mdx mice but never in control animals. One intravenously injected 4-wk-old animal showed large areas of dye uptake into the  myocardium (a), whereas in other mice, smaller regions of EBD-positive fibers were found in the ventricular walls (b). Cardiac  dye uptake in intraperitoneally injected mdx mice (c, 10-mo-old  animal) demonstrated that the fiber damage was caused by the  underlying disease and not by a volume overload of intravenously  administered dye, leading to a cardiac infarct. Bars, 100 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2139791&req=5

Figure 3: EBD staining on 7-μm cryosections of mdx cardiac muscle. EBD-positive cardiomyocytes were detected in 8 out of 16 mdx mice but never in control animals. One intravenously injected 4-wk-old animal showed large areas of dye uptake into the myocardium (a), whereas in other mice, smaller regions of EBD-positive fibers were found in the ventricular walls (b). Cardiac dye uptake in intraperitoneally injected mdx mice (c, 10-mo-old animal) demonstrated that the fiber damage was caused by the underlying disease and not by a volume overload of intravenously administered dye, leading to a cardiac infarct. Bars, 100 μm.
Mentions: We also examined cardiac muscle from all injected animals, since cardiac involvement is a common feature in many forms of muscular dystrophy. Control mice never showed EBD-positive fibers in cardiac muscle tissue. In contrast, 8 out of 16 mdx mice had EBD-positive lesions in the myocardium. In one 4-wk-old mouse, large areas of the cardiac section showed EBD uptake into cardiac muscle fibers (Fig. 3 a), whereas in the other mice, ranging from 6 to 52 wk of age, regions of variable size in the ventricular wall were affected (Fig. 3, b and c). On sections stained with H&E, the EBD-positive areas showed characteristic features of myocardial damage, with a strong inflammatory component (data not shown). Myocardial EBD staining in intraperitoneally injected mice (Fig. 3 c) provided evidence that the fiber damage was caused by the underlying disease and not by volume overload of intravenously administered dye, leading to a cardiac infarct.

Bottom Line: However, little is known about how alterations in the DGC are manifested in the pathophysiology present in dystrophic muscle tissue.One hypothesis is that the DGC protects the sarcolemma from contraction-induced damage.Taken together, these results suggest that the pathogenic mechanisms in congenital muscular dystrophy are different from those in Duchenne muscular dystrophy, although the primary defects originate in two components associated with the same protein complex.

View Article: PubMed Central - PubMed

Affiliation: Department of, Howard Hughes Medical Institute, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.

ABSTRACT
Genetic defects in a number of components of the dystrophin-glycoprotein complex (DGC) lead to distinct forms of muscular dystrophy. However, little is known about how alterations in the DGC are manifested in the pathophysiology present in dystrophic muscle tissue. One hypothesis is that the DGC protects the sarcolemma from contraction-induced damage. Using tracer molecules, we compared sarcolemmal integrity in animal models for muscular dystrophy and in muscular dystrophy patient samples. Evans blue, a low molecular weight diazo dye, does not cross into skeletal muscle fibers in normal mice. In contrast, mdx mice, a dystrophin-deficient animal model for Duchenne muscular dystrophy, showed significant Evans blue accumulation in skeletal muscle fibers. We also studied Evans blue dispersion in transgenic mice bearing different dystrophin mutations, and we demonstrated that cytoskeletal and sarcolemmal attachment of dystrophin might be a necessary requirement to prevent serious fiber damage. The extent of dye incorporation in transgenic mice correlated with the phenotypic severity of similar dystrophin mutations in humans. We furthermore assessed Evans blue incorporation in skeletal muscle of the dystrophia muscularis (dy/dy) mouse and its milder allelic variant, the dy2J/dy2J mouse, animal models for congenital muscular dystrophy. Surprisingly, these mice, which have defects in the laminin alpha2-chain, an extracellular ligand of the DGC, showed little Evans blue accumulation in their skeletal muscles. Taken together, these results suggest that the pathogenic mechanisms in congenital muscular dystrophy are different from those in Duchenne muscular dystrophy, although the primary defects originate in two components associated with the same protein complex.

Show MeSH
Related in: MedlinePlus