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Article Dans Une Revue Disease Models & Mechanisms Année : 2012

Myotubular myopathy and the neuromuscular junction: a novel therapeutic approach from mouse models

James Dowling
  • Fonction : Auteur
Romain Joubert
  • Fonction : Auteur
Sean Low
  • Fonction : Auteur
Ashley Durban
  • Fonction : Auteur
Nadia Messaddeq
  • Fonction : Auteur
Xingli Li
  • Fonction : Auteur
Ashley Dulin-Smith
  • Fonction : Auteur
Andrew Snyder
  • Fonction : Auteur
Morgan Marshall
  • Fonction : Auteur
Jordan Marshall
  • Fonction : Auteur
Alan Beggs
  • Fonction : Auteur
Anna Buj-Bello
Christopher Pierson
  • Fonction : Auteur

Résumé

Summary 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.

Dates et versions

hal-04481738 , version 1 (28-02-2024)

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Citer

James Dowling, Romain Joubert, Sean Low, Ashley Durban, Nadia Messaddeq, et al.. Myotubular myopathy and the neuromuscular junction: a novel therapeutic approach from mouse models. Disease Models & Mechanisms, 2012, ⟨10.1242/dmm.009746⟩. ⟨hal-04481738⟩
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