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

Proceedings of the National Academy of Sciences - PNAS, 2009-11, Vol.106 (44), p.18763-18768 [Peer Reviewed Journal]

Copyright National Academy of Sciences Nov 3, 2009 ;Distributed under a Creative Commons Attribution 4.0 International License ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.0900705106 ;PMID: 19846786

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Title:
T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase
Author: 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
Subjects: Animals ; Biochemistry, Molecular Biology ; Biological Sciences ; Calcium ; Calcium - metabolism ; Calcium Channels - metabolism ; Cell membranes ; Gene Expression Regulation ; Homeostasis - genetics ; Ion Channel Gating ; Life Sciences ; Lipid Metabolism ; Lipids ; Membranes ; Mice ; Mice, Knockout ; Molecular biology ; Molecular structure ; Muscle Contraction - physiology ; Muscle fibers ; Muscle Fibers, Skeletal - enzymology ; Muscle Fibers, Skeletal - pathology ; Muscle Fibers, Skeletal - ultrastructure ; Muscles ; Muscular diseases ; Musculoskeletal system ; Mutation ; Phosphatases ; Phosphatidylinositols ; Plasma ; Protein Tyrosine Phosphatases, Non-Receptor - deficiency ; Protein Tyrosine Phosphatases, Non-Receptor - metabolism ; Receptors ; Rodents ; Sarcoplasmic Reticulum - enzymology ; Sarcoplasmic Reticulum - pathology ; Sarcoplasmic Reticulum - ultrastructure ; Skeletal muscle
Is Part Of: Proceedings of the National Academy of Sciences - PNAS, 2009-11, Vol.106 (44), p.18763-18768
Description: 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 Ca²⁺ release elicited by voltage-clamp depolarizations is strongly depressed in myotubularin-deficient 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.
Publisher: United States: National Academy of Sciences
Language: English
Identifier: ISSN: 0027-8424
EISSN: 1091-6490
DOI: 10.1073/pnas.0900705106
PMID: 19846786
Source: Geneva Foundation Free Medical Journals at publisher websites
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T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase

Copyright National Academy of Sciences Nov 3, 2009 ;Distributed under a Creative Commons Attribution 4.0 International License ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.0900705106 ;PMID: 19846786

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