Abstract
OBJECTIVE: Congenital muscular dystrophy type 1A is an autosomal recessive disease that is caused by loss-of-function mutations in the laminin-alpha2 gene, and results in motor nerve and skeletal muscle dysfunction. In a previous study, we used genetic modifications to show that inappropriate induction of apoptosis was a significant contributor to pathogenesis in a laminin-alpha2-deficient mouse model of congenital muscular dystrophy type 1A. To identify a possible pharmacological therapy for laminin-alpha2 deficiency, we designed this study to determine whether treatment with minocycline or doxycycline, which are tetracycline derivatives reported to have antiapoptotic effects in mammals, would significantly increase lifespan and improve neuromuscular function in laminin-alpha2-deficient mice. METHODS: Mice that were homozygous for a targeted, inactivating mutation of the laminin-alpha2 gene were placed into control, minocycline-treated, or doxycycline-treated groups. Drug treatment began within 2 weeks of birth, and the progression of disease was followed over time using behavioral, growth, histological, and molecular assays. RESULTS: We found that treatment with either minocycline or doxycycline increased the median lifespan of laminin-alpha2-null mice from approximately 32 days to approximately 70 days. Furthermore, doxycycline improved postnatal growth rate and delayed the onset of hind-limb paralysis. Doxycycline-treated laminin-alpha2-deficient muscles had increased Akt phosphorylation, decreased inflammation, and decreased levels of Bax protein, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive myonuclei, and activated caspase-3. INTERPRETATION: Doxycycline or other drugs with similar functional profiles may be a possible route to improving neuromuscular dysfunction caused by laminin-alpha2-deficiency.