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T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase
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T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase
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Journal Article
T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase
2009
Overview
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
National Academy of Sciences,National Acad Sciences
Subject
/ Animals
/ Biochemistry, Molecular Biology
/ Calcium
/ Calcium Channels - metabolism
/ genes
/ Lipids
/ Mice
/ Muscle Contraction - physiology
/ Muscle Fibers, Skeletal - enzymology
/ Muscle Fibers, Skeletal - pathology
/ Muscle Fibers, Skeletal - ultrastructure
/ Muscles
/ Mutation
/ Plasma
/ Protein Tyrosine Phosphatases, Non-Receptor - deficiency
/ Protein Tyrosine Phosphatases, Non-Receptor - metabolism
/ Rodents
/ Sarcoplasmic Reticulum - enzymology
/ Sarcoplasmic Reticulum - pathology
