Signaling and molecular mechanisms of myofibrillogenesis participating in muscle regeneration and muscle and cardiac hypertrophy

本研究旨在阐明肌原纤维肌动蛋白细丝形成的信号和分子机制。我们发现N-WASP结合在心肌原纤维Z带的星云SH3结构域(NEBT)。NEBT-N-WASP复合体使肌动蛋白成核，从Z带形成肌动蛋白细丝。此外，Lmod2结合在NEBT的N-末端区域，似乎延长了由NEBT-N-WASP复合体形成的肌动蛋白短丝。GSK-3β使NEBT C-末端区域、N-WASP和Lmod2磷酸化，可能导致它们失活或降解。腹主动脉缩窄可引起小鼠病理性心肌肥大、纤维化和心功能恶化。给小鼠注射IGF-1可以改善这些症状，而N-WASP抑制剂则加剧了这些症状。因此，由IGF-1信号激活的N-WASP诱导的肌动蛋白细丝的形成是正常心脏功能所必需的，因为它干扰了病理的心脏表型。

This research project aimed to elucidate signaling and molecular mechanisms of myofibrillar actin filament formation. We found that N-WASP bound to the SH3 domain of nebulette (Nebt) in the Z bands of cardiac myofibrils. The Nebt-N-WASP complex nucleated actin to form actin filaments from the Z-bands. Furthermore, Lmod2 bound to N-terminal region of Nebt and seemed to extend short actin filaments preformed by the Nebt-N-WASP complex. GSK-3beta phosphorylated Nebt C-terminal region, N-WASP, and Lmod2, possibly resulting in their inactivation or degradation. Transverse aortic constriction caused pathological cardiac hypertrophy, fibrosis, and deterioration of cardiac function in mice. Administration of IGF-1 to mice ameliorated these symptoms, whereas that of an N-WASP inhibitor worsened them. Thus, actin filament formation induced by N-WASP activated by IGF-1 signaling is required for normal cardiac functions by interfering with pathological cardiac phenotypes.