Nebulin and N-WASP Cooperate to Cause IGF-1–Induced Sarcomeric Actin Filament Formation

Kazunori Takano,^1,2 Haruko Watanabe-Takano,^1,2 Shiro Suetsugu,^2,3,4 Souichi Kurita,^1,* Kazuya Tsujita,⁵ Sumiko Kimura,¹ Takashi Karatsu,⁶ Tadaomi Takenawa,^2,5 Takeshi Endo^1,2,

Abstract: Insulin-like growth factor 1 (IGF-1) induces skeletal muscle maturation and enlargement (hypertrophy). These responses require protein synthesis and myofibril formation (myofibrillogenesis). However, the signaling mechanisms of myofibrillogenesis remain obscure. We found that IGF-1–induced phosphatidylinositol 3-kinase–Akt signaling formed a complex of nebulin and N-WASP at the Z bands of myofibrils by interfering with glycogen synthase kinase-3β in mice. Although N-WASP is known to be an activator of the Arp2/3 complex to form branched actin filaments, the nebulin–N-WASP complex caused actin nucleation for unbranched actin filament formation from the Z bands without the Arp2/3 complex. Furthermore, N-WASP was required for IGF-1–induced muscle hypertrophy. These findings present the mechanisms of IGF-1–induced actin filament formation in myofibrillogenesis required for muscle maturation and hypertrophy and a mechanism of actin nucleation.

¹ Department of Biology, Graduate School of Science, Chiba University, 1-33 Yayoicho, Inageku, Chiba 263-8522, Japan.
² Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Chiyodaku, Tokyo 102-0075, Japan.
³ Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
⁴ Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Chiyodaku, Tokyo 102-0075, Japan.
⁵ Division of Lipid Biochemistry, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
⁶ Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoicho, Inageku, Chiba 263-8522, Japan.

To whom correspondence should be addressed. E-mail: t.endo{at}faculty.chiba-u.jp

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