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

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Science  10 Dec 2010:
Vol. 330, Issue 6010, pp. 1536-1540
DOI: 10.1126/science.1197767

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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.

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