Article
Author: Ladha, Feria A. ; Elhelaly, Waleed M. ; Nguyen, Ngoc Uyen Nhi ; Li, Shujuan ; Luo, Xiang ; Pereira, Ana Helena Macedo ; Sadek, Hesham A. ; Hsu, Ching-Cheng ; Sadayappan, Sakthivel ; Kanchwala, Mohammed ; Kimura, Wataru ; Hajjar, Roger J. ; Lam, Nicholas T. ; Singh, Rohit ; Menendez-Montes, Ivan ; Hinson, J. Travis ; Cardoso, Alisson Campos ; Wang, Ping ; Xing, Chao ; Hill, Joseph A. ; Thet, Suwannee ; Xiao, Feng
BACKGROUND:Recent interest in understanding cardiomyocyte cell cycle has been driven by potential therapeutic applications in cardiomyopathy. However, despite recent advances, cardiomyocyte mitosis remains a poorly understood process. For example, it is unclear how sarcomeres are disassembled during mitosis to allow the abscission of daughter cardiomyocytes.METHODS:Here, we use a proteomics screen to identify adducin, an actin capping protein previously not studied in cardiomyocytes, as a regulator of sarcomere disassembly. We generated many adeno-associated viruses and cardiomyocyte-specific genetic gain-of-function models to examine the role of adducin in neonatal and adult cardiomyocytes in vitro and in vivo.RESULTS:We identify adducin as a regulator of sarcomere disassembly during mammalian cardiomyocyte mitosis. α/γ-adducins are selectively expressed in neonatal mitotic cardiomyocytes, and their levels decline precipitously thereafter. Cardiomyocyte-specific overexpression of various splice isoforms and phospho-isoforms of α-adducin in vitro and in vivo identified Thr445/Thr480 phosphorylation of a short isoform of α-adducin as a potent inducer of neonatal cardiomyocyte sarcomere disassembly. Concomitant overexpression of this α-adducin variant along with γ-adducin resulted in stabilization of the adducin complex and persistent sarcomere disassembly in adult mice, which is mediated by interaction with α-actinin.CONCLUSIONS:These results highlight an important mechanism for coordinating cytoskeletal morphological changes during cardiomyocyte mitosis.