Abstract
SUMMARYMyotubular 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.
Highlights
Myotubular myopathy (MTM), an X-linked congenital myopathy, is among the most severe childhood neuromuscular disorders (Jungbluth et al, 2008)
Using a zebrafish model of MTM, we recently demonstrated that mtm1 knockdown disturbs neuromuscular junction (NMJ) organization and that exposure to an Myotubular myopathy and the neuromuscular junction acetylcholinesterase inhibitor improves motor function in morphant embryos (Robb et al, 2011)
MTM mice have phenotypic and neurodiagnostic features of a disorder of NMJ transmission We evaluated these models for evidence of a clinical disorder of NMJ transmission
Summary
Myotubular myopathy (MTM), an X-linked congenital myopathy, is among the most severe childhood neuromuscular disorders (Jungbluth et al, 2008). Affected boys usually present in infancy with hypotonia, weakness and respiratory failure, and nearly half die in the first year of life (Herman et al, 2002; McEntagart et al, 2002). Those who survive have substantial disability, most often never achieving independent ambulation and usually requiring continuous ventilator support, and suffer premature lethality. MTM is the most common subtype of a larger group of childhood muscle diseases called centronuclear myopathies (CNMs) (Jungbluth et al, 2008).
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