Pathology is alleviated by doxycycline in a laminin-α2–null model of congenital muscular dystrophy
Article first published online: 11 DEC 2008
Copyright © 2008 American Neurological Association
Annals of Neurology
Volume 65, Issue 1, pages 47–56, January 2009
How to Cite
Girgenrath, M., Beermann, M. L., Vishnudas, V. K., Homma, S. and Miller, J. B. (2009), Pathology is alleviated by doxycycline in a laminin-α2–null model of congenital muscular dystrophy. Ann Neurol., 65: 47–56. doi: 10.1002/ana.21523
- Issue published online: 12 FEB 2009
- Article first published online: 11 DEC 2008
- Manuscript Accepted: 15 AUG 2008
- Manuscript Revised: 4 AUG 2008
- Manuscript Received: 11 APR 2008
- Muscular Dystrophy Association of the U.S.A.
- NIDMS. Grant Number: AR049496
- NHLBI. Grant Number: HL064641
Congenital muscular dystrophy type 1A is an autosomal recessive disease that is caused by loss-of-function mutations in the laminin-α2 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-α2–deficient mouse model of congenital muscular dystrophy type 1A. To identify a possible pharmacological therapy for laminin-α2 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-α2–deficient mice.
Mice that were homozygous for a targeted, inactivating mutation of the laminin-α2 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.
We found that treatment with either minocycline or doxycycline increased the median lifespan of laminin-α2–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-α2–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.
Doxycycline or other drugs with similar functional profiles may be a possible route to improving neuromuscular dysfunction caused by laminin-α2-deficiency. Ann Neurol 2008