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

Research output: Contribution to journalArticle

104 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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Excitation Contraction Coupling
Sarcoplasmic Reticulum
Phosphoric Monoester Hydrolases
Ryanodine Receptor Calcium Release Channel
Congenital Structural Myopathies
Lipids
Muscles
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Muscle Contraction
Endocytosis
Skeletal Muscle
Homeostasis
Maintenance
Cell Membrane
Mutation
Membranes
myotubularin
Genes
Proteins

Keywords

  • Myotubular myopathy
  • Triad

ASJC Scopus subject areas

  • General

Cite this

T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase. / Al-Qusairi, Lama; Weiss, Norbert; Toussaint, Anne; Berbey, Céline; Messaddeq, Nadia; Kretz, Christine; Sanoudou, Despina; Beggs, Alan H.; Allard, Bruno; Mandel, Jean Louis; Laporte, Jocelyn; Jacquemond, Vincent; Buj-Bello, Anna.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 44, 03.11.2009, p. 18763-18768.

Research output: Contribution to journalArticle

Al-Qusairi, L, Weiss, N, Toussaint, A, Berbey, C, Messaddeq, N, Kretz, C, Sanoudou, D, Beggs, AH, Allard, B, Mandel, JL, 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, vol. 106, no. 44, pp. 18763-18768. https://doi.org/10.1073/pnas.0900705106
Al-Qusairi, Lama ; Weiss, Norbert ; Toussaint, Anne ; Berbey, Céline ; Messaddeq, Nadia ; Kretz, Christine ; Sanoudou, Despina ; Beggs, Alan H. ; Allard, Bruno ; Mandel, Jean Louis ; Laporte, Jocelyn ; Jacquemond, Vincent ; Buj-Bello, Anna. / T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 44. pp. 18763-18768.
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AU - Messaddeq, Nadia

AU - Kretz, Christine

AU - Sanoudou, Despina

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