title: Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy.
abstract: The most common form of human congenital muscular dystrophy (CMD) is caused by mutations in the laminin-alpha2 gene. Loss of laminin-alpha2 function in this autosomal recessive type 1A form of CMD results in neuromuscular dysfunction and, often, early death. Laminin-alpha2-deficient skeletal muscles in both humans and mice show signs of muscle cell death by apoptosis. To examine the significance of apoptosis in CMD1A pathogenesis, we determined whether pathogenesis in laminin-alpha2-deficient (Lama2(-/-)) mice could be ameliorated by inhibiting apoptosis through either (a) inactivation of the proapoptosis protein Bax or (b) overexpression of the antiapoptosis protein Bcl-2 from a muscle-specific transgene. We found that both of these genetic interventions produced a several-fold increase in the lifespan of Lama2(-/-) mice. Bax inactivation also improved postnatal growth rate and myofiber histology and decreased fixed contractures of Lama2(-/-) mice. Thus, Bcl-2 family-mediated apoptosis contributes significantly to pathogenesis in the mouse model of CMD1A, and antiapoptosis therapy may be a possible route to amelioration of neuromuscular dysfunction due to laminin-alpha2 deficiency in humans.
authors.affiliation: Neuromuscular Biology and Disease Group, Boston Biomedical Research Institute, Watertown, Massachusetts 02478, USA.
authors.forename: Mahasweta
authors.initials: M
authors.lastname: Girgenrath
authors.forename: Janice A
authors.initials: JA
authors.lastname: Dominov
authors.forename: Christine A
authors.initials: CA
authors.lastname: Kostek
authors.forename: Jeffrey Boone
authors.initials: JB
authors.lastname: Miller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019938:Cyclin D1 / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000473:pathology / Q000502:physiology; D009136:Muscular Dystrophies / Q000151:congenital* / Q000378:metabolism*; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019076:Transgenes; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; C494827:Bax protein, mouse; D007797:Laminin; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C102645:laminin alpha 2; D019938:Cyclin D1