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

Masaki Tsuchiya, Yuji Hara (), Masaki Okuda, Karin Itoh, Ryotaro Nishioka, Akifumi Shiomi, Kohjiro Nagao, Masayuki Mori, Yasuo Mori, Junichi Ikenouchi, Ryo Suzuki, Motomu Tanaka, Tomohiko Ohwada, Junken Aoki, Motoi Kanagawa, Tatsushi Toda, Yosuke Nagata, Ryoichi Matsuda, Yasunori Takayama, Makoto Tominaga and Masato Umeda ()
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Masaki Tsuchiya: Graduate School of Engineering, Kyoto University
Yuji Hara: Graduate School of Engineering, Kyoto University
Masaki Okuda: Graduate School of Engineering, Kyoto University
Karin Itoh: Graduate School of Engineering, Kyoto University
Ryotaro Nishioka: Graduate School of Engineering, Kyoto University
Akifumi Shiomi: Graduate School of Engineering, Kyoto University
Kohjiro Nagao: Graduate School of Engineering, Kyoto University
Masayuki Mori: Graduate School of Engineering, Kyoto University
Yasuo Mori: Graduate School of Engineering, Kyoto University
Junichi Ikenouchi: Kyushu University
Ryo Suzuki: Kyoto University
Motomu Tanaka: Kyoto University
Tomohiko Ohwada: The University of Tokyo
Junken Aoki: Tohoku University
Motoi Kanagawa: Kobe University Graduate School of Medicine
Tatsushi Toda: The University of Tokyo
Yosuke Nagata: Okayama University of Science
Ryoichi Matsuda: The University of Tokyo
Yasunori Takayama: Okazaki Institute for Integrative Bioscience
Makoto Tominaga: Okazaki Institute for Integrative Bioscience
Masato Umeda: Graduate School of Engineering, Kyoto University

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04436-w

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