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Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2009

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

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

Résumé

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 Ca 2+ release elicited by voltage-clamp depolarizations is strongly depressed in myotubularin-deficient muscle fibers, with myoplasmic Ca 2+ removal and SR Ca 2+ 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 Ca 2+ release is responsible for the failure of muscle function in myotubular myopathy.

Dates et versions

hal-04481757 , version 1 (28-02-2024)

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Citer

Lama Al-Qusairi, Norbert Weiss, Anne Toussaint, Céline Berbey, Nadia Messaddeq, et al.. 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, 2009, 106 (44), pp.18763-18768. ⟨10.1073/pnas.0900705106⟩. ⟨hal-04481757⟩
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