T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase.
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.
Department of Neurobiology and Genetics, and Imaging Center-Electron Microscopy, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U964, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 7104, Université Louis Pasteur, Collège de France, 67404 Illkirch, France.
Lama
L
Al-Qusairi
Norbert
N
Weiss
Anne
A
Toussaint
Céline
C
Berbey
Nadia
N
Messaddeq
Christine
C
Kretz
Despina
D
Sanoudou
Alan H
AH
Beggs
Bruno
B
Allard
Jean-Louis
JL
Mandel
Jocelyn
J
Laporte
Vincent
V
Jacquemond
Anna
A
Buj-Bello
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics; D015640:Ion Channel Gating; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000172:deficiency* / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure
D015220:Calcium Channels; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin; D002118:Calcium