Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models.

Abstract

Humans and mice with deficiency of the ␣ 2 subunit of the basement membrane protein laminin-2/merosin suffer from merosin-deficient congenital muscular dystrophy (MCMD). We have expressed a human laminin ␣ 2 chain transgene under the regulation of a muscle-specific creatine kinase promoter in mice with complete or partial deficiency of merosin. The transgene restores the synthesis and localization of merosin in skeletal muscle, and greatly improves muscle morphology and integrity and the health and longevity of the mice. However, the transgenic mice share with the nontransgenic dystrophic mice a progressive lameness of hind legs, suggestive of a nerve defect. These results indicate that the absence of merosin in tissues other than the muscle, such as nervous tissue, is a critical component of MCMD.

Myoblast transplantations lead to the expression of the laminin α2 chain in normal and dystrophic (dy/dy) mouse muscles

“…Indeed, the muscles of dystrophic animals, both spontaneous mutants and knock-out models, are formed at birth, but present regeneration defects. 23,24 Our data, however, clearly indicate that myotubes and myofibers were formed in vivo in the absence of detectable amounts of the laminin ␣2 chain and thus suggest that the presence of laminin-2 is not an absolute prerequisite for myoblast fusion in vivo. Interestingly, the lack of laminin-2 did not increase acute cell death following cell injection, since D7LNB1 cells survived and were able to participate in muscle regeneration.…”

“…As shown in Figure 1, 1 month after transplantation, the human laminin ␣2 chain was detected around small, medium and normal diameter muscle fibers at the injection sites using the 5H2 antibody which does not react with mouse laminin-2 ( Figure 1a and b). 24 Large clusters of muscle fibers expressing the human laminin ␣2 chain were observed (Figure 1a and c). However, it must be noted that no human laminin ␣2 was expressed by muscle fibers located at a distance from the injection sites in the tibialis mouse muscle (Figure 1a), indicating: (1) that the pure human cells did not repopulate the whole mouse muscle, and (2) that the distribution of the human proteins was restricted to the injection site.…”

“…21,22 Two knock-out mouse models have been described recently. 23,24 We have shown previously that the transplantation of primary mouse muscle cell cultures partially restored laminin ␣2 chain expression in dy/dy mice. 25 However, due to the heterogenous nature of these primary cultures, it was not possible to identify unambiguously the cell type responsible for this laminin ␣2 chain restoration.…”

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

“…From 1994, knock-out mouse or spontaneous mutant mouse strains have been identified as animal models for MDC1A with total and partial deficiency [99][100][101][102][103][104][105] , and experimental therapeutic strategies have been attempted 102,103,[106][107][108][109][110][111][112][113][114][115][116] . In mice, Kuang et al 102,103 were successful in obtaining the expression of a human laminin alpha 2 chain transgene under the regulation of a muscle-specific creatine kinase promoter.…”

“…In mice, Kuang et al 102,103 were successful in obtaining the expression of a human laminin alpha 2 chain transgene under the regulation of a muscle-specific creatine kinase promoter. They detected the synthesis of laminin alpha-2 in muscle and a marked improvement of the clinical and histopathological changes; however, there was no improvement of the peripheral neuropathy and they concluded that potential new therapies have to be also directed to restore laminin alpha-2 in other tissue as CNs and peripheral nerves.…”