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 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.

中文翻译：

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内收蛋白调节心肌细胞有丝分裂期间的肌节分解


背景：最近对了解心肌细胞周期的兴趣是由心肌病的潜在治疗应用驱动的。然而，尽管最近取得了进展，但心肌细胞有丝分裂仍然是一个人们知之甚少的过程。例如，尚不清楚肌节在有丝分裂过程中如何分解以允许子代心肌细胞脱落。方法：在这里，我们使用蛋白质组学筛选来鉴定内收蛋白（一种以前未在心肌细胞中研究过的肌动蛋白加帽蛋白）作为肌节分解的调节剂。我们生成了许多腺相关病毒和心肌细胞特异性遗传功能获得模型，以在体外和体内检查内收蛋白在新生儿和成人心肌细胞中的作用。结果：我们确定内收蛋白是哺乳动物心肌细胞有丝分裂期间肌节解体的调节剂。 α/γ-内收蛋白在新生儿有丝分裂心肌细胞中选择性表达，此后其水平急剧下降。心肌细胞特异性过度表达 α-内收蛋白的各种剪接亚型和磷酸亚型，确定了 α-内收蛋白短亚型的 Thr445/Thr480 磷酸化作为新生儿心肌细胞肌节解体的有效诱导剂。这种 α-内收蛋白变体与 γ-内收蛋白同时过度表达导致成年小鼠中内收蛋白复合物的稳定和持续的肌节分解，这是通过与 α-肌动蛋白的相互作用介导的。 结论：这些结果强调了协调细胞骨架形态的重要机制心肌细胞有丝分裂过程中的变化。