title: Transient Ca2+ depletion from the endoplasmic reticulum is critical for skeletal myoblast differentiation.
abstract: Endoplasmic reticulum (ER) stress is a cellular condition in which unfolded proteins accumulate in the ER because of various but specific causes. Physiologic ER stress occurs transiently during myoblast differentiation, and although its cause remains unknown, it plays a critical role in myofiber formation. To examine the mechanism underlying ER stress, we monitored ER morphology during differentiation of murine myoblasts. Novel ER-derived structures transiently appeared prior to myoblast fusion both in vitro and in vivo. Electron microscopy studies revealed that these structures consisted of pseudoconcentric ER cisternae with narrow lumens. Similar structures specifically formed by pharmacologically induced ER Ca(2+) depletion, and inhibition of ER Ca(2+) efflux channels in differentiating myoblasts considerably suppressed ER-specific deformation and ER stress signaling. Thus, we named the novel structures stress-activated response to Ca(2+) depletion (SARC) bodies. Prior to SARC body formation, stromal interaction molecule 1 (STIM1), an ER Ca(2+) sensor protein, formed ER Ca(2+) depletion-specific clusters. Furthermore, myoblast differentiation manifested by myoblast fusion did not proceed under the same conditions as inhibition of ER Ca(2+) depletion. Altogether, these observations suggest that ER Ca(2+) depletion is a prerequisite for myoblast fusion, causing both physiologic ER stress signaling and SARC body formation.
authors: *Molecular Membrane Biology Laboratory, RIKEN Advanced Science Institute, Wako, Saitama, Japan; Electron Microscope Laboratory, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan; and Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo, Japan.
authors: Keiko
authors: K
authors: Nakanishi
authors: *Molecular Membrane Biology Laboratory, RIKEN Advanced Science Institute, Wako, Saitama, Japan; Electron Microscope Laboratory, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan; and Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo, Japan.
authors: Kisa
authors: K
authors: Kakiguchi
authors: *Molecular Membrane Biology Laboratory, RIKEN Advanced Science Institute, Wako, Saitama, Japan; Electron Microscope Laboratory, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan; and Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo, Japan.
authors: Shigenobu
authors: S
authors: Yonemura
authors: *Molecular Membrane Biology Laboratory, RIKEN Advanced Science Institute, Wako, Saitama, Japan; Electron Microscope Laboratory, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan; and Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo, Japan.
authors: Akihiko
authors: A
authors: Nakano
authors: *Molecular Membrane Biology Laboratory, RIKEN Advanced Science Institute, Wako, Saitama, Japan; Electron Microscope Laboratory, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan; and Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo, Japan morishim@riken.jp.
authors: Nobuhiro
authors: N
authors: Morishima
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D007124:Immunoenzyme Techniques; D051379:Mice; D032448:Myoblasts, Skeletal / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D002118:Calcium
keywords: ER deformation; ER stress; STIM1; myoblast fusion