Τίτλος:
T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Al-Qusairi, L.
Weiss, N.
Toussaint, A.
Berbey, C.
Messaddeq, N.
Kretz, C.
Sanoudou, D.
Beggs, A.H.
Allard, B.
Mandel, J.-L.
Laporte, J.
Jacquemond, V.
Buj-Bello, A.
Περιοδικό:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
Λέξεις-κλειδιά:
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
DOI:
10.1073/pnas.0900705106
