%0 Journal Article %J Proc Natl Acad Sci U S AProc Natl Acad Sci U S AProc Natl Acad Sci U S A %D 2009 %T T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase %A Al-Qusairi, L. %A Weiss, N. %A Toussaint, A. %A Berbey, C. %A Messaddeq, N. %A Kretz, C. %A Sanoudou, D. %A Beggs, A. H. %A Allard, B. %A Mandel, J. L. %A Laporte, J. %A Jacquemond, V. %A Buj-Bello, A. %K *Lipid Metabolism %K Animals %K Calcium Channels/metabolism %K Calcium/metabolism %K Gene Expression Regulation %K Homeostasis/genetics %K Ion Channel Gating %K Mice %K Mice, Knockout %K Muscle Contraction/*physiology %K Muscle Fibers, Skeletal/*enzymology/*pathology/ultrastructure %K Protein Tyrosine Phosphatases, Non-Receptor/*deficiency/metabolism %K Sarcoplasmic Reticulum/*enzymology/*pathology/ultrastructure %X 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. %B Proc Natl Acad Sci U S AProc Natl Acad Sci U S AProc Natl Acad Sci U S A %V 106 %P 18763-8 %8 Nov 3 %@ 1091-6490 (Electronic)0027-8424 (Linking) %G eng %M 19846786 %2 2773964 %! Proceedings of the National Academy of Sciences of the United States of AmericaProceedings of the National Academy of Sciences of the United States of America