T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase

Lama Al-Qusairi, Norbert Weiss, Anne Toussaint, Céline Berbey, Nadia Messaddeq, Christine Kretz, Despina Sanoudou, Alan H. Beggs, Bruno Allard, Jean Louis Mandel, Jocelyn Laporte, Vincent Jacquemond, Anna Buj-Bello

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105 Citations (Scopus)

Abstract

Skeletal muscle contraction is triggered by the excitation-contra-ction (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 character-ized. 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 myo-tubularin, 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-defi-cient 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.

Original languageEnglish
Pages (from-to)18763-18768
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number44
DOIs
Publication statusPublished - 3 Nov 2009
Externally publishedYes

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Keywords

  • Myotubular myopathy
  • Triad

ASJC Scopus subject areas

  • General

Cite this

Al-Qusairi, L., Weiss, N., Toussaint, A., Berbey, C., Messaddeq, N., Kretz, C., Sanoudou, D., Beggs, A. H., Allard, B., Mandel, J. L., Laporte, J., Jacquemond, V., & Buj-Bello, A. (2009). T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase. Proceedings of the National Academy of Sciences of the United States of America, 106(44), 18763-18768. https://doi.org/10.1073/pnas.0900705106