Cell surface flip-flop of phosphatidylserine is critical for PIEZO1-mediated myotube formation

Nat Commun. 2018 May 24;9(1):2049. doi: 10.1038/s41467-018-04436-w.

Masaki Tsuchiya ¹, Yuji Hara ² ³, Masaki Okuda ¹, Karin Itoh ¹, Ryotaro Nishioka ¹, Akifumi Shiomi ¹, Kohjiro Nagao ¹, Masayuki Mori ¹, Yasuo Mori ¹, Junichi Ikenouchi ⁴, Ryo Suzuki ⁵ ⁶, Motomu Tanaka ⁵ ⁷ ⁶, Tomohiko Ohwada ⁸, Junken Aoki ⁹, Motoi Kanagawa ¹⁰, Tatsushi Toda ¹¹, Yosuke Nagata ¹², Ryoichi Matsuda ¹³, Yasunori Takayama ¹⁴, Makoto Tominaga ¹⁴, Masato Umeda ¹⁵

Affiliations

1 Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, 615-8510, Japan.
2 Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, 615-8510, Japan. [email protected].
3 AMED-PRIME, Japan Agency for Medical Research and Development, Tokyo, 100-0004, Japan. [email protected].
4 Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, 819-0395, Japan.
5 Institute for Integrated Cell-Material Sciences (WPI iCeMS), Kyoto University, Kyoto, 606-8501, Japan.
6 Center for Integrative Medicine and Physics, Institute for Advanced Study, Kyoto University, Kyoto, 606-8501, Japan.
7 Physical Chemistry of Biosystems, Institute of Physical Chemistry, University of Heidelberg, Heidelberg, 69120, Germany.
8 Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 115-0033, Japan.
9 Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, 980-8578, Japan.
10 Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan.
11 Department of Neurology, Division of Neuroscience, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
12 Department of Life Science, Faculty of Science, Okayama University of Science, Okayama, 700-0005, Japan.
13 Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, 153-8902, Japan.
14 Division of Cell Signaling, Okazaki Institute for Integrative Bioscience, Aichi, 444-8787, Japan.
15 Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, 615-8510, Japan. [email protected].

PMID: 29799007 DOI: 10.1038/s41467-018-04436-w

Abstract

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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