心肌细胞可以通过从脂肪酸氧化转变为糖酵解来适应病理性应激引起的能量危机。然而,接受心脏手术的患者使用葡萄糖-胰岛素-钾(GIK)溶液并不能缓解缺血/再灌注(I/R)引起的能量短缺.这表明胰岛素介导的葡萄糖转运蛋白4(Glut-4)的易位在缺血性心脏中受损。的确,心肌细胞包含两个细胞内Glut-4群体:胰岛素依赖性非内体池(也称为Glut-4储存囊泡,GSVs)和不依赖胰岛素的内体池。肿瘤易感基因101(Tsg101)与膜蛋白的内体再循环有关。在这项研究中,我们旨在检查Tsg101是否在基础和缺血条件下调节Glut-4向心肌细胞肌膜的分选和再分布,使用功能增益和损失方法。在小鼠心脏和分离的心肌细胞中强制过表达Tsg101可以促进Glut-4重新分布到肌膜,导致I/R心脏中葡萄糖进入和三磷酸腺苷(ATP)的生成增强,I/R诱导的心功能不全的衰减。相反,心肌细胞中Tsg101的敲低表现出相反的作用。机械上,我们发现Tsg101可以与Glut-4相互作用并共同定位在心肌细胞的肌膜中。我们的发现将Tsg101定义为心脏Glut-4贩运的新型调节剂,可能为缺血性心脏病的治疗提供新的治疗策略。
Cardiac cells can adapt to pathological stress-induced energy crisis by shifting from fatty acid oxidation to glycolysis. However, the use of glucose-insulin-potassium (GIK) solution in patients undergoing cardiac surgery does not alleviate ischemia/reperfusion (I/R)-induced energy shortage. This indicates that insulin-mediated translocation of glucose transporter-4 (Glut-4) is impaired in ischemic hearts. Indeed, cardiac myocytes contain two intracellular populations of Glut-4: an insulin-dependent non-endosomal pool (also referred to as Glut-4 storage vesicles, GSVs) and an insulin-independent endosomal pool. Tumor susceptibility gene 101 (Tsg101) has been implicated in the endosomal recycling of membrane proteins. In this study, we aimed to examine whether Tsg101 regulated the sorting and re-distribution of Glut-4 to the
sarcolemma membrane of cardiomyocytes under basal and ischemic conditions, using gain- and loss-of-function approaches. Forced overexpression of Tsg101 in mouse hearts and isolated cardiomyocytes could promote Glut-4 re-distribution to the
sarcolemma, leading to enhanced glucose entry and adenosine triphosphate (ATP) generation in I/R hearts which in turn, attenuation of I/R-induced cardiac dysfunction. Conversely, knockdown of Tsg101 in cardiac myocytes exhibited opposite effects. Mechanistically, we identified that Tsg101 could interact and co-localize with Glut-4 in the
sarcolemma membrane of cardiomyocytes. Our findings define Tsg101 as a novel regulator of cardiac Glut-4 trafficking, which may provide a new therapeutic strategy for the treatment of ischemic heart disease.