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.