TY - JOUR
T1 - Cell surface flip-flop of phosphatidylserine is critical for PIEZO1-mediated myotube formation
AU - Tsuchiya, Masaki
AU - Hara, Yuji
AU - Okuda, Masaki
AU - Itoh, Karin
AU - Nishioka, Ryotaro
AU - Shiomi, Akifumi
AU - Nagao, Kohjiro
AU - Mori, Masayuki
AU - Mori, Yasuo
AU - Ikenouchi, Junichi
AU - Suzuki, Ryo
AU - Tanaka, Motomu
AU - Ohwada, Tomohiko
AU - Aoki, Junken
AU - Kanagawa, Motoi
AU - Toda, Tatsushi
AU - Nagata, Yosuke
AU - Matsuda, Ryoichi
AU - Takayama, Yasunori
AU - Tominaga, Makoto
AU - Umeda, Masato
N1 - Funding Information:
We thank S. Sawada, K. Akiyoshi, T. Tamura, and I. Hamachi (Kyoto University) for valuable advice and technical assistance. We thank Kyoto University Live Imaging Center for time-lapse observations. pMXs-puro vector and a retrovirus packaging cell line Plat-E were kind gifts from T. Kitamura (the University of Tokyo). We thank the Wellcome Trust Sanger Institute Mouse Genetics Project (Sanger MGP) and its funders for providing the mutant mouse line (Atp11atm1a(KOMP)Wtsi). Funding information may be found at www.sanger.ac.uk/mouseportal and associated primary phenotypic information at www.mousephenotype.org. This study was supported in part by Grants-in-Aid for Scientific Research on Innovative Areas (15H05930 to M.U.); Fund for the Promotion of Joint International Research (15K21744 to M.U.); Grants-in-Aid for Scientific Research (KAKENHI) (25293012, 17H03805 to M.U.; 15H04846 to Y.H.) from Japan Society for the Promotion of Science (JSPS) and Ministry of Education, Culture, Sports, Science and Technology (MEXT); AMED-PRIME from Japan Agency for Medical Research and Development (JP17gm5810016 to Y.H.); intramural research grants (26-8, 29-4) for neurological and psychiatric disorders of NCNP (to Y.H.); Grant-in-Aid for JSPS Research Fellow (16J11409 to M.Ts.); and grants from the Takeda science and Ono medical research foundations (to Y.H.).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Myotube formation by fusion of myoblasts and subsequent elongation of the syncytia is essential for skeletal muscle formation. However, molecules that regulate myotube formation remain elusive. Here we identify PIEZO1, a mechanosensitive Ca2+ channel, as a key regulator of myotube formation. During myotube formation, phosphatidylserine, a phospholipid that resides in the inner leaflet of the plasma membrane, is transiently exposed to cell surface and promotes myoblast fusion. We show that cell surface phosphatidylserine inhibits PIEZO1 and that the inward translocation of phosphatidylserine, which is driven by the phospholipid flippase complex of ATP11A and CDC50A, is required for PIEZO1 activation. PIEZO1-mediated Ca2+ influx promotes RhoA/ROCK-mediated actomyosin assemblies at the lateral cortex of myotubes, thus preventing uncontrolled fusion of myotubes and leading to polarized elongation during myotube formation. These results suggest that cell surface flip-flop of phosphatidylserine acts as a molecular switch for PIEZO1 activation that governs proper morphogenesis during myotube formation.
AB - Myotube formation by fusion of myoblasts and subsequent elongation of the syncytia is essential for skeletal muscle formation. However, molecules that regulate myotube formation remain elusive. Here we identify PIEZO1, a mechanosensitive Ca2+ channel, as a key regulator of myotube formation. During myotube formation, phosphatidylserine, a phospholipid that resides in the inner leaflet of the plasma membrane, is transiently exposed to cell surface and promotes myoblast fusion. We show that cell surface phosphatidylserine inhibits PIEZO1 and that the inward translocation of phosphatidylserine, which is driven by the phospholipid flippase complex of ATP11A and CDC50A, is required for PIEZO1 activation. PIEZO1-mediated Ca2+ influx promotes RhoA/ROCK-mediated actomyosin assemblies at the lateral cortex of myotubes, thus preventing uncontrolled fusion of myotubes and leading to polarized elongation during myotube formation. These results suggest that cell surface flip-flop of phosphatidylserine acts as a molecular switch for PIEZO1 activation that governs proper morphogenesis during myotube formation.
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U2 - 10.1038/s41467-018-04436-w
DO - 10.1038/s41467-018-04436-w
M3 - Article
C2 - 29799007
AN - SCOPUS:85047608191
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2049
ER -