Journal
DISEASE MODELS & MECHANISMS
Volume 5, Issue 6, Pages 852-859Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dmm.009746
Keywords
-
Categories
Funding
- Muscular Dystrophy Association [MDA 186999, MDA 201302, MDA 155638]
- Taubman Medical Institute
- National Institutes of Health [NIH 1K08AR054835, NIH K08NS49095, R01AR044345]
- Joshua Frase Foundation
- Lee and Penny Anderson Family Foundation
- Association Francaise contre les Myopathies (AFM)
- Myotubular Trust
- ATIGE-Genopole d'Evry, France
Ask authors/readers for more resources
Myotubular myopathy (MTM) is a severe congenital muscle disease characterized by profound weakness, early respiratory failure and premature lethality. MTM is defined by muscle biopsy findings that include centralized nuclei and disorganization of perinuclear organelles. No treatments currently exist for MTM. We hypothesized that aberrant neuromuscular junction (NMJ) transmission is an important and potentially treatable aspect of the disease pathogenesis. We tested this hypothesis in two murine models of MTM. In both models we uncovered evidence of a disorder of NMJ transmission: fatigable weakness, improved strength with neostigmine, and electrodecrement with repetitive nerve stimulation. Histopathological analysis revealed abnormalities in the organization, appearance and size of individual NMJs, abnormalities that correlated with changes in acetylcholine receptor gene expression and subcellular localization. We additionally determined the ability of pyridostigmine, an acetylcholinesterase inhibitor, to ameliorate aspects of the behavioral phenotype related to NMJ dysfunction. Pyridostigmine treatment resulted in significant improvement in fatigable weakness and treadmill endurance. In all, these results describe a newly identified pathological abnormality in MTM, and uncover a potential disease-modifying therapy for this devastating disorder.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available