title: Pathology is alleviated by doxycycline in a laminin-alpha2-null model of congenital muscular dystrophy.
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.
  
  
  CONCLUSIONS
  Doxycycline or other drugs with similar functional profiles may be a possible route to improving neuromuscular dysfunction caused by laminin-alpha2-deficiency.
authors.affiliation: Department of Health Sciences, Boston University, Boston, MA, USA.
authors.forename: Mahasweta
authors.initials: M
authors.lastname: Girgenrath
authors.forename: Mary Lou
authors.initials: ML
authors.lastname: Beermann
authors.forename: Vivek K
authors.initials: VK
authors.lastname: Vishnudas
authors.forename: Sachiko
authors.initials: S
authors.lastname: Homma
authors.forename: Jeffrey Boone
authors.initials: JB
authors.lastname: Miller
mesh_terms: D000367:Age Factors; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D039481:CD11b Antigen / Q000378:metabolism; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007797:Laminin / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D016019:Survival Analysis; D013912:Threonine / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D039481:CD11b Antigen; D004791:Enzyme Inhibitors; D007797:Laminin; C102645:laminin alpha 2; D013912:Threonine; D051057:Proto-Oncogene Proteins c-akt; D019311:Staurosporine; D004318:Doxycycline