HOME / PUBLICATIONS /

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

Citation:

Al-Qusairi L, Weiss N, Toussaint A, Berbey C, Messaddeq N, Kretz C, Sanoudou D, Beggs AH, Allard B, Mandel JL, et al. T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase. Proc Natl Acad Sci U S AProc Natl Acad Sci U S AProc Natl Acad Sci U S A. 2009;106:18763-8.

Abstract:

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.

Notes:

Al-Qusairi, LamaWeiss, NorbertToussaint, AnneBerbey, CelineMessaddeq, NadiaKretz, ChristineSanoudou, DespinaBeggs, Alan HAllard, BrunoMandel, Jean-LouisLaporte, JocelynJacquemond, VincentBuj-Bello, AnnaengP50 NS040828/NS/NINDS NIH HHS/P50 NS040828-080003/NS/NINDS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't2009/10/23 06:00Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18763-8. doi: 10.1073/pnas.0900705106. Epub 2009 Oct 21.