Limits...
Loss of myotubularin function results in T-tubule disorganization in zebrafish and human myotubular myopathy.

Dowling JJ, Vreede AP, Low SE, Gibbs EM, Kuwada JY, Bonnemann CG, Feldman EL - PLoS Genet. (2009)

Bottom Line: Zebrafish with reduced levels of myotubularin have significantly impaired motor function and obvious histopathologic changes in their muscle.We demonstrate for the first time that myotubularin functions to regulate PI3P levels in a vertebrate in vivo, and that homologous myotubularin-related proteins can functionally compensate for the loss of myotubularin.Based on our findings, we speculate that congenital myopathies, usually considered entities with similar clinical features but very disparate pathomechanisms, may at their root be disorders of calcium homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan, USA. jamedowl@umich.edu

ABSTRACT
Myotubularin is a lipid phosphatase implicated in endosomal trafficking in vitro, but with an unknown function in vivo. Mutations in myotubularin cause myotubular myopathy, a devastating congenital myopathy with unclear pathogenesis and no current therapies. Myotubular myopathy was the first described of a growing list of conditions caused by mutations in proteins implicated in membrane trafficking. To advance the understanding of myotubularin function and disease pathogenesis, we have created a zebrafish model of myotubular myopathy using morpholino antisense technology. Zebrafish with reduced levels of myotubularin have significantly impaired motor function and obvious histopathologic changes in their muscle. These changes include abnormally shaped and positioned nuclei and myofiber hypotrophy. These findings are consistent with those observed in the human disease. We demonstrate for the first time that myotubularin functions to regulate PI3P levels in a vertebrate in vivo, and that homologous myotubularin-related proteins can functionally compensate for the loss of myotubularin. Finally, we identify abnormalities in the tubulo-reticular network in muscle from myotubularin zebrafish morphants and correlate these changes with abnormalities in T-tubule organization in biopsies from patients with myotubular myopathy. In all, we have generated a new model of myotubular myopathy and employed this model to uncover a novel function for myotubularin and a new pathomechanism for the human disease that may explain the weakness associated with the condition (defective excitation-contraction coupling). In addition, our findings of tubuloreticular abnormalities and defective excitation-contraction coupling mechanistically link myotubular myopathy with several other inherited muscle diseases, most notably those due to ryanodine receptor mutations. Based on our findings, we speculate that congenital myopathies, usually considered entities with similar clinical features but very disparate pathomechanisms, may at their root be disorders of calcium homeostasis.

Show MeSH

Related in: MedlinePlus

Ultrastructural changes in T-tubules in myotubular myopathy.Electron microscopic analysis of muscle from 3 myotubular myopathy patients (MTM) and one age-matched control (CTL). Control T-tubule triads are discretely formed (arrow), and the adjacent SR network is thin and well organized. Triads and adjacent SR from patient biopsies are dilated and disorganized. Scale bar = 500 nm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2631153&req=5

pgen-1000372-g012: Ultrastructural changes in T-tubules in myotubular myopathy.Electron microscopic analysis of muscle from 3 myotubular myopathy patients (MTM) and one age-matched control (CTL). Control T-tubule triads are discretely formed (arrow), and the adjacent SR network is thin and well organized. Triads and adjacent SR from patient biopsies are dilated and disorganized. Scale bar = 500 nm.

Mentions: We lastly examined electron micrographs obtained from patient muscle biopsies (Figure 12). Age matched control muscle showed the typical tight triad structure with well-organized adjacent sarcoplasmic reticulum. In contrast, micrographs from 3 myotubular myopathy patients showed various degrees of dilatation and disorganization of the T-tubules and adjacent sarcoplasmic reticulum. In conjunction with the immunostaining, these data confirm that T-tubule abnormalities are present in both our zebrafish model and in patients with myotubular myopathy.


Loss of myotubularin function results in T-tubule disorganization in zebrafish and human myotubular myopathy.

Dowling JJ, Vreede AP, Low SE, Gibbs EM, Kuwada JY, Bonnemann CG, Feldman EL - PLoS Genet. (2009)

Ultrastructural changes in T-tubules in myotubular myopathy.Electron microscopic analysis of muscle from 3 myotubular myopathy patients (MTM) and one age-matched control (CTL). Control T-tubule triads are discretely formed (arrow), and the adjacent SR network is thin and well organized. Triads and adjacent SR from patient biopsies are dilated and disorganized. Scale bar = 500 nm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2631153&req=5

pgen-1000372-g012: Ultrastructural changes in T-tubules in myotubular myopathy.Electron microscopic analysis of muscle from 3 myotubular myopathy patients (MTM) and one age-matched control (CTL). Control T-tubule triads are discretely formed (arrow), and the adjacent SR network is thin and well organized. Triads and adjacent SR from patient biopsies are dilated and disorganized. Scale bar = 500 nm.
Mentions: We lastly examined electron micrographs obtained from patient muscle biopsies (Figure 12). Age matched control muscle showed the typical tight triad structure with well-organized adjacent sarcoplasmic reticulum. In contrast, micrographs from 3 myotubular myopathy patients showed various degrees of dilatation and disorganization of the T-tubules and adjacent sarcoplasmic reticulum. In conjunction with the immunostaining, these data confirm that T-tubule abnormalities are present in both our zebrafish model and in patients with myotubular myopathy.

Bottom Line: Zebrafish with reduced levels of myotubularin have significantly impaired motor function and obvious histopathologic changes in their muscle.We demonstrate for the first time that myotubularin functions to regulate PI3P levels in a vertebrate in vivo, and that homologous myotubularin-related proteins can functionally compensate for the loss of myotubularin.Based on our findings, we speculate that congenital myopathies, usually considered entities with similar clinical features but very disparate pathomechanisms, may at their root be disorders of calcium homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan, USA. jamedowl@umich.edu

ABSTRACT
Myotubularin is a lipid phosphatase implicated in endosomal trafficking in vitro, but with an unknown function in vivo. Mutations in myotubularin cause myotubular myopathy, a devastating congenital myopathy with unclear pathogenesis and no current therapies. Myotubular myopathy was the first described of a growing list of conditions caused by mutations in proteins implicated in membrane trafficking. To advance the understanding of myotubularin function and disease pathogenesis, we have created a zebrafish model of myotubular myopathy using morpholino antisense technology. Zebrafish with reduced levels of myotubularin have significantly impaired motor function and obvious histopathologic changes in their muscle. These changes include abnormally shaped and positioned nuclei and myofiber hypotrophy. These findings are consistent with those observed in the human disease. We demonstrate for the first time that myotubularin functions to regulate PI3P levels in a vertebrate in vivo, and that homologous myotubularin-related proteins can functionally compensate for the loss of myotubularin. Finally, we identify abnormalities in the tubulo-reticular network in muscle from myotubularin zebrafish morphants and correlate these changes with abnormalities in T-tubule organization in biopsies from patients with myotubular myopathy. In all, we have generated a new model of myotubular myopathy and employed this model to uncover a novel function for myotubularin and a new pathomechanism for the human disease that may explain the weakness associated with the condition (defective excitation-contraction coupling). In addition, our findings of tubuloreticular abnormalities and defective excitation-contraction coupling mechanistically link myotubular myopathy with several other inherited muscle diseases, most notably those due to ryanodine receptor mutations. Based on our findings, we speculate that congenital myopathies, usually considered entities with similar clinical features but very disparate pathomechanisms, may at their root be disorders of calcium homeostasis.

Show MeSH
Related in: MedlinePlus