T-tubule Disorganization and Defective Excitation-Contraction Coupling in Muscle Fibers Lacking Myotubularin Lipid Phosphatase

Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18763-8. doi: 10.1073/pnas.0900705106. Epub 2009 Oct 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Muscle Fibers, Skeletal / pathology*
  • Muscle Fibers, Skeletal / ultrastructure
  • Protein Tyrosine Phosphatases, Non-Receptor / deficiency*
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism
  • Sarcoplasmic Reticulum / enzymology*
  • Sarcoplasmic Reticulum / pathology*
  • Sarcoplasmic Reticulum / ultrastructure

Substances

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