Activation of the lama2 gene in muscle regeneration: Abortive regenerationin laminin alpha 2-deficiency

Mutations in laminin alpha 2, a subunit of the basement membrane protein la minin-2/merosin, cause merosin-deficient congenital muscular dystrophy. To gain insight into the molecular mechanism of disease, we generated and used a mutant mouse, dy(W), in which the lacZ gene was inserted into the lama2 gene so that beta-galactosidase would be expressed in place of laminin alph a 2. Heterozygous and homozygous mutant mice are normal at birth, but homoz ygous mice develop muscular dystrophy at 2 to 3 weeks of age. The lama2/lac Z gene was highly expressed in muscle in the early stages of embryonic myog enesis, but was down-regulated at later stages in both heterozygous and hom ozygous mice. No beta-galactosidase activity was detected in skeletal muscl e after birth in adult heterozygous mice. In contrast, high beta-galactosid ase activity was detected in postnatal homozygous mice. Induction of injury in heterozygous mice resulted in intense reexpression of beta-galactosidas e in the injured muscle early in regeneration, with a decline in enzyme act ivity as repair of the tissue progressed. Although the initial response to injury was similar in heterozygous and homozygous mice with abundant beta-g alactosidase-positive, mononucleated cells in the injured area, repair was rarely completed in the homozygous mice, evidently caused by excessive deat h of cells associated with immature myofibers. The defect in muscle repair was very efficiently corrected in homozygous dy(W) mice expressing a human LAMA2 transgene in skeletal muscle. The data show the importance of laminin alpha 2 in muscle regeneration and suggest that a major contributor to dis ease in muscular dystrophy is abortive regeneration.