Xiao, FengNguyen, Ngoc Uyen NhiWang, PingLi, ShujuanHsu, Ching-ChengThet, SuwanneeKimura, WataruLuo, XiangLam, Nicholas TMenendez-Montes, IvanElhelaly, WaleedCardoso, Alisson CamposPereira, Ana Helena MacedoSingh, RohitSadayappan, SakthivelKanchwala, MohammedXing, ChaoLadha, Feria AHinson, J TravisHajjar, Roger JHill, Joseph ASadek, Hesham A2024-07-032024-07-032024-05-06Circulation. 2024 May 6.http://hdl.handle.net/20.500.12105/19935BACKGROUND 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 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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 Internacional3870863510.1161/CIRCULATIONAHA.122.0591021524-4539Circulationopen access