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

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.

• Authors: Lama Al-Qusairi, Norbert Weiss, Anne Toussaint, Céline Berbey, Nadia Messaddeq, Christine Kretz, Despina Sanoudou, Alan H Beggs, Bruno Allard, Jean-Louis Mandel, Jocelyn Laporte, Vincent Jacquemond, Anna Buj-Bello
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 44 Pg. 18763-8 (Nov 03 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19846786 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channels
• Protein Tyrosine Phosphatases, Non-Receptor
• myotubularin
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium Channels (metabolism)
• Gene Expression Regulation
• Homeostasis (genetics)
• Ion Channel Gating
• Lipid Metabolism
• Mice
• Mice, Knockout
• Muscle Contraction (physiology)
• Muscle Fibers, Skeletal (enzymology, pathology, ultrastructure)
• Protein Tyrosine Phosphatases, Non-Receptor (deficiency, metabolism)
• Sarcoplasmic Reticulum (enzymology, pathology, ultrastructure)