ANIMAL-MODELS FOR MUSCULAR-DYSTROPHY SHOW DIFFERENT PATTERNS OF SARCOLEMMAL DISRUPTION

Genetic defects in a number of components of the dystrophin-glycoprote in complex (DGC) lead to distinct forms of muscular dystrophy. However , little is known about how alterations in the DGC are manifested in t he pathophysiology present in dystrophic muscle tissue. One hypothesis is that the DGC protects the sarcolemma from contraction-induced dama ge. Using tracer molecules, we compared sarcolemmal integrity in anima l models for muscular dystrophy and in muscular dystrophy patient samp les. Evans blue, a low molecular weight diazo dye, does not cross into skeletal muscle fibers in normal mice. In contrast, mdx mice, a dystr ophin-deficient animal model for Duchenne muscular dystrophy, showed s ignificant Evans blue accumulation in skeletal muscle fibers. We also studied Evans blue dispersion in transgenic mice bearing different dys trophin mutations, and we demonstrated that cytoskeletal and sarcolemm al attachment of dystrophin might be a necessary requirement to preven t serious fiber damage. The extent of dye incorporation in transgenic mice correlated with the phenotypic severity of similar dystrophin mut ations in humans. We furthermore assessed Evans blue incorporation in skeletal muscle of the dystrophia muscularis (dy/dy) mouse and its mil der allelic variant, the dy(2J)/dy(2J) mouse, animal models for congen ital muscular dystrophy. Surprisingly, these mice, which have defects in the laminin alpha 2-chain, an extracellular ligand of the DGC, show ed little Evans blue accumulation in their skeletal muscles. Taken tog ether, these results suggest that the pathogenic mechanisms in congeni tal muscular dystrophy are different from those in Duchenne muscular d ystrophy, although the primary defects originate in two components ass ociated with the same protein complex.