Myocardial failure is associated with adverse remodeling, which includes apoptotic loss of cardiomyocytes, hypertrophy, as well as alterations in cell–cell contacts. Striatin-interacting phosphatase and kinase (STRIPAK) complexes and their kinase mammalian STE20-like kinase 4 (Mst4) have been linked to the development of different diseases. The role and targets of Mst4 in cardiomyocytes have not been investigated yet. Multitissue immunoblot experiments show highly enriched Mst4 expression in rodent hearts. Analyses of human biopsy samples from patients suffering from dilated cardiomyopathy revealed that Mst4 is upregulated (5- to 8-fold < 0.001) compared with nonfailing controls. Increased abundance of Mst4 could also be detected in mouse models of cardiomyopathy. We confirmed that Mst4 interacts with STRIPAK components in neonatal rat ventricular cardiomyocytes, indicating that STRIPAK is present in the heart. Immunofluorescence stainings and molecular interaction studies revealed that Mst4 is localized to the intercalated disc and interacts with several intercalated disc proteins. Overexpression of Mst4 in neonatal rat cardiomyocytes results in hypertrophy compared with controls. In adult rat cardiomyocytes, Mst4 overexpression increases cellular and sarcomeric fractional shortening ( < 0.05), indicating enhanced contractility. Overexpression of Mst4 also inhibits apoptotic cell death shown by reduction of cleaved caspase3 (−69%, < 0.0001) and caspase7 (−80%, < 0.0001) as well as cleaved Parp1 (−27%, < 0.001). To elucidate potential Mst4 targets, we performed phosphoproteomics analyses in neonatal rat cardiomyocytes after Mst4 overexpression and inhibition. The results revealed several target candidates of Mst4 at the intercalated disc and sarcolemma. We identified Mst4 as a novel cardiac kinase that is upregulated in human cardiomyopathy and regulates cardiomyocyte growth and survival.

中文翻译：

---

Mst4 是一种新型心脏 STRIPAK 复合物相关激酶，可调节心肌细胞生长和存活，并在人类心肌病中表达上调

心肌衰竭与不良重塑相关，包括心肌细胞凋亡损失、肥大以及细胞间接触的改变。条纹蛋白相互作用磷酸酶和激酶 (STRIPAK) 复合物及其激酶哺乳动物 STE20 样激酶 4 (Mst4) 与不同疾病的发展有关。 Mst4 在心肌细胞中的作用和靶点尚未得到研究。多组织免疫印迹实验显示啮齿动物心脏中高度富集的 Mst4 表达。对扩张型心肌病患者的人体活检样本的分析表明，与正常对照组相比，Mst4 表达上调（5 至 8 倍 < 0.001）。在小鼠心肌病模型中也可以检测到 Mst4 丰度的增加。我们证实 Mst4 与新生大鼠心室心肌细胞中的 STRIPAK 成分相互作用，表明 STRIPAK 存在于心脏中。免疫荧光染色和分子相互作用研究表明，Mst4 定位于闰盘并与多种闰盘蛋白相互作用。与对照组相比，新生大鼠心肌细胞中 Mst4 的过度表达导致心肌细胞肥大。在成年大鼠心肌细胞中，Mst4 过表达会增加细胞和肌节缩短分数 (< 0.05)，表明收缩性增强。 Mst4 的过表达还可以抑制细胞凋亡，具体表现为裂解的 caspase3 (−69%，< 0.0001) 和 caspase7 (−80%，< 0.0001) 以及裂解的 Parp1 (−27%，< 0.001) 的减少。为了阐明潜在的 Mst4 靶标，我们在 Mst4 过表达和抑制后对新生大鼠心肌细胞进行了磷酸蛋白质组学分析。结果揭示了 Mst4 在闰盘和肌膜处的几个候选靶点。我们确定 Mst4 是一种新型心肌激酶，在人类心肌病中表达上调，并调节心肌细胞的生长和存活。