Rao Krithika, Rochon Elizabeth, Singh Anuradha, Jagannathan Rajaganapathi, Peng Zishan, Mansoor Haris, Wang Bing, Moulik Mousumi, Zhang Manling, Saraf Anita, Corti Paola, Shiva Sruti
Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Division of Cardiology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15261, USA.
iScience. 2024 Feb 6;27(3):109146. doi: 10.1016/j.isci.2024.109146. eCollection 2024 Mar 15.
The endogenous mechanisms that propagate cardiomyocyte differentiation and prevent de-differentiation remain unclear. While the expression of the heme protein myoglobin increases by over 50% during cardiomyocyte differentiation, a role for myoglobin in regulating cardiomyocyte differentiation has not been tested. Here, we show that deletion of myoglobin in cardiomyocyte models decreases the gene expression of differentiation markers and stimulates cellular proliferation, consistent with cardiomyocyte de-differentiation. Mechanistically, the heme prosthetic group of myoglobin catalyzes the oxidation of the Hippo pathway kinase LATS1, resulting in phosphorylation and inactivation of yes-associated protein (YAP). , myoglobin-deficient zebrafish hearts show YAP dephosphorylation and accelerated cardiac regeneration after apical injury. Similarly, myoglobin knockdown in neonatal murine hearts shows increased YAP dephosphorylation and cardiomyocyte cycling. These data demonstrate a novel role for myoglobin as an endogenous driver of cardiomyocyte differentiation and highlight myoglobin as a potential target to enhance cardiac development and improve cardiac repair and regeneration.
促进心肌细胞分化并防止去分化的内源性机制仍不清楚。虽然在心肌细胞分化过程中，血红素蛋白肌红蛋白的表达增加了50%以上，但肌红蛋白在调节心肌细胞分化中的作用尚未得到验证。在这里，我们表明，在心肌细胞模型中删除肌红蛋白会降低分化标志物的基因表达，并刺激细胞增殖，这与心肌细胞去分化一致。从机制上讲，肌红蛋白的血红素辅基催化Hippo通路激酶LATS1的氧化，导致Yes相关蛋白（YAP）磷酸化并失活。此外，肌红蛋白缺陷的斑马鱼心脏在顶端损伤后显示YAP去磷酸化和心脏再生加速。同样，新生小鼠心脏中的肌红蛋白敲低显示YAP去磷酸化增加和心肌细胞循环。这些数据证明了肌红蛋白作为心肌细胞分化内源性驱动因子的新作用，并突出了肌红蛋白作为增强心脏发育和改善心脏修复与再生的潜在靶点。
