T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase
AUTOR(ES)
Al-Qusairi, Lama
FONTE
National Academy of Sciences
RESUMO
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 Ca2+ release elicited by voltage-clamp depolarizations is strongly depressed in myotubularin-deficient 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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2773964Documentos Relacionados
- Extracellular ions and excitation-contraction coupling in frog twitch muscle fibres.
- Activation and inactivation of excitation-contraction coupling in rat soleus muscle.
- Gradient in excitation-contraction coupling in canine gastric antral circular muscle.
- Mechano-sensitive linkage in excitation-contraction coupling in frog skeletal muscle.
- Valinomycin and excitation-contraction coupling in skeletal muscle fibres of the frog.