Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 44, Pages 18763-18768Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0900705106
Keywords
myotubular myopathy; triad
Categories
Funding
- Institut National de la Santeet de la Recherche Medicale
- Centre National de la Recherche Scientifique
- Hopital Universitaire de Strasbourg (HUS)
- College de France
- Association Franc, aise contre les Myopathies (AFM)
- Agence Nationale de la Recherche (ANR)
- Fondation pour la RechercheMedicale (FRM)
- National Institutes of Health [P50 NS040828]
- Joshua Frase Foundation
- Lee and Penny Anderson Family Foundation
- Syrian Ministry of High Education
- FRM
Ask authors/readers for more resources
Skeletal muscle contraction is triggered by the excitation-contraction (E-C) coupling machinery residing at the triad, a membrane structure formed by the juxtaposition of T-tubules and sarcoplasmic reticulum (SR) cisternae. The formation and maintenance of this structure is key for muscle function but is not well characterized. We have investigated the mechanisms leading to X-linked myotubular myopathy (XLMTM), a severe congenital disorder due to loss of function mutations in the MTM1 gene, encoding myotubularin, a phosphoinositide phosphatase thought to have a role in plasma membrane homeostasis and endocytosis. Using a mouse model of the disease, we report that Mtm1-deficient muscle fibers have a decreased number of triads and abnormal longitudinally oriented T-tubules. In addition, SR Ca2+ release elicited by voltage-clamp depolarizations is strongly depressed in myotubularin-deficient muscle fibers, with myoplasmic Ca2+ removal and SR Ca2+ content essentially unaffected. At the molecular level, Mtm1-deficient myofibers exhibit a 3-fold reduction in type 1 ryanodine receptor (RyR1) protein level. These data reveal a critical role of myotubularin in the proper organization and function of the E-C coupling machinery and strongly suggest that defective RyR1-mediated SR Ca2+ release is responsible for the failure of muscle function in myotubular myopathy.
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