title: Myotubularin and PtdIns3P remodel the sarcoplasmic reticulum in muscle in vivo.
abstract: The sarcoplasmic reticulum (SR) is a specialized form of endoplasmic reticulum (ER) in skeletal muscle and is essential for calcium homeostasis. The mechanisms involved in SR remodeling and maintenance of SR subdomains are elusive. In this study, we identified myotubularin (MTM1), a phosphoinositide phosphatase mutated in X-linked centronuclear myopathy (XLCNM, or myotubular myopathy), as a key regulator of phosphatidylinositol 3-monophosphate (PtdIns3P) levels at the SR. MTM1 is predominantly located at the SR cisternae of the muscle triads, and Mtm1-deficient mouse muscles and myoblasts from XLCNM patients exhibit abnormal SR/ER networks. In vivo modulation of MTM1 enzymatic activity in skeletal muscle using ectopic expression of wild-type or a dead-phosphatase MTM1 protein leads to differential SR remodeling. Active MTM1 is associated with flat membrane stacks, whereas dead-phosphatase MTM1 mutant promotes highly curved cubic membranes originating from the SR and enriched in PtdIns3P. Overexpression of a tandem FYVE domain with high affinity for PtdIns3P alters the shape of the SR cisternae at the triad. Our findings, supported by the parallel analysis of the Mtm1-null mouse and an in vivo study, reveal a direct function of MTM1 enzymatic activity in SR remodeling and a key role for PtdIns3P in promoting SR membrane curvature in skeletal muscle. We propose that alteration in SR remodeling is a primary cause of X-linked centronuclear myopathy. The tight regulation of PtdIns3P on specific membrane subdomains may be a general mechanism to control membrane curvature.
authors: Department of Translational Medicine, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Université de Strasbourg, Collège de France, 67404 Illkirch, France.
authors: Leonela
authors: L
authors: Amoasii
authors: Karim
authors: K
authors: Hnia
authors: Gaëtan
authors: G
authors: Chicanne
authors: Andreas
authors: A
authors: Brech
authors: Belinda S
authors: BS
authors: Cowling
authors: Martin Michael
authors: MM
authors: Müller
authors: Yannick
authors: Y
authors: Schwab
authors: Pascale
authors: P
authors: Koebel
authors: Arnaud
authors: A
authors: Ferry
authors: Bernard
authors: B
authors: Payrastre
authors: Jocelyn
authors: J
authors: Laporte
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D011485:Protein Binding; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D018129:Phosphatidylinositol Phosphates; C055525:phosphatidylinositol 3-phosphate; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin
keywords: MTM1; Membrane remodeling; PI3P; PtdIns3P; Sarcoplasmic reticulum