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.