TY - JOUR
TI - T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase
AU - Al-Qusairi, L.
AU - Weiss, N.
AU - Toussaint, A.
AU - Berbey, C.
AU - Messaddeq, N.
AU - Kretz, C.
AU - Sanoudou, D.
AU - Beggs, A.H.
AU - Allard, B.
AU - Mandel, J.-L.
AU - Laporte, J.
AU - Jacquemond, V.
AU - Buj-Bello, A.
JO - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
PY - 2009
VL - 106
TODO - 44
SP - 18763-18768
PB - 
SN - null
TODO - 10.1073/pnas.0900705106
TODO - calcium channel;  calcium ion;  myotubularin lipid phosphatase;  phosphatase;  ryanodine receptor;  unclassified drug, animal experiment;  animal model;  animal tissue;  article;  calcium homeostasis;  calcium transport;  cell membrane;  centronuclear myopathy;  controlled study;  endocytosis;  gene;  gene control;  gene function;  gene mutation;  male;  mouse;  mtm1 gene;  muscle cell;  muscle contraction;  muscle excitation;  muscle weakness;  nonhuman;  priority journal;  sarcoplasmic reticulum;  transverse tubular system;  voltage clamp;  X chromosome linked disorder, Animals;  Calcium;  Calcium Channels;  Gene Expression Regulation;  Homeostasis;  Ion Channel Gating;  Lipid Metabolism;  Mice;  Mice, Knockout;  Muscle Contraction;  Muscle Fibers, Skeletal;  Protein Tyrosine Phosphatases, Non-Receptor;  Sarcoplasmic Reticulum
TODO - 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.
ER -