BACKGROUND Exercise intolerance is an independent predictor of poor prognosis in diabetes. The underlying mechanism of the association between hyperglycemia and exercise intolerance remains undefined. We recently demonstrated that the interaction between ARRDC4 (arrestin domain-containing protein 4) and GLUT1 (glucose transporter 1) regulates cardiac metabolism. METHODS To determine whether this mechanism broadly impacts diabetic complications, we investigated the role of ARRDC4 in the pathogenesis of diabetic cardiac/skeletal myopathy using cellular and animal models. RESULTS High glucose promoted translocation of MondoA into the nucleus, which upregulated Arrdc4 transcriptional expression, increased lysosomal GLUT1 trafficking, and blocked glucose transport in cardiomyocytes, forming a feedback mechanism. This role of ARRDC4 was confirmed in human muscular cells from type 2 diabetic patients. Prolonged hyperglycemia upregulated myocardial Arrdc4 expression in multiple types of mouse models of diabetes. We analyzed hyperglycemia-induced cardiac and skeletal muscle abnormalities in insulin-deficient mice. Hyperglycemia increased advanced glycation end-products and elicited oxidative and endoplasmic reticulum stress leading to apoptosis in the heart and peripheral muscle. Deletion of Arrdc4 augmented tissue glucose transport and mitochondrial respiration, protecting the heart and muscle from tissue damage. Stress hemodynamic analysis and treadmill exhaustion test uncovered that Arrdc4-knockout mice had greater cardiac inotropic/chronotropic reserve with higher exercise endurance than wild-type animals under diabetes. While multiple organs were involved in the mechanism, cardiac-specific overexpression using an adenoassociated virus suggests that high levels of myocardial ARRDC4 have the potential to contribute to exercise intolerance by interfering with cardiac metabolism through its interaction with GLUT1 in diabetes. Importantly, the ARRDC4 mutation mouse line exhibited greater exercise tolerance, showing the potential therapeutic impact on diabetic cardiomyopathy by disrupting the interaction between ARRDC4 and GLUT1. CONCLUSIONS ARRDC4 regulates hyperglycemia-induced toxicities toward cardiac and skeletal muscle, revealing a new molecular framework that connects hyperglycemia to cardiac/skeletal myopathy to exercise intolerance.

中文翻译：

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系统性删除 ARRDC4 可改善糖尿病患者的心脏储备和运动能力。


背景运动不耐受是糖尿病预后不良的独立预测因素。高血糖和运动不耐受之间关联的潜在机制仍不清楚。我们最近证明 ARRDC4（含抑制蛋白结构域的蛋白 4）和 GLUT1（葡萄糖转运蛋白 1）之间的相互作用可调节心脏代谢。方法 为了确定这种机制是否广泛影响糖尿病并发症，我们使用细胞和动物模型研究了 ARRDC4 在糖尿病心脏/骨骼肌病发病机制中的作用。结果高糖促进MondoA转入细胞核，上调Arrdc4转录表达，增加溶酶体GLUT1转运，阻断心肌细胞内葡萄糖转运，形成反馈机制。 ARRDC4 的这种作用在 2 型糖尿病患者的人类肌肉细胞中得到了证实。在多种类型的糖尿病小鼠模型中，长期高血糖会上调心肌 Arrdc4 表达。我们分析了胰岛素缺乏小鼠中高血糖引起的心肌和骨骼肌异常。高血糖增加晚期糖基化终产物，引发氧化和内质网应激，导致心脏和外周肌肉细胞凋亡。 Arrdc4 的缺失增强了组织葡萄糖转运和线粒体呼吸，保护心脏和肌肉免受组织损伤。应激血流动力学分析和跑台疲劳试验发现，与糖尿病下的野生型动物相比，Arrdc4 敲除小鼠具有更大的强心力/变时性储备和更高的运动耐力。 虽然该机制涉及多个器官，但使用腺相关病毒进行的心脏特异性过度表达表明，高水平的心肌 ARRDC4 有可能通过与糖尿病中的 GLUT1 相互作用来干扰心脏代谢，从而导致运动不耐受。重要的是，ARRDC4 突变小鼠系表现出更高的运动耐量，通过破坏 ARRDC4 和 GLUT1 之间的相互作用显示出对糖尿病心肌病的潜在治疗作用。结论 ARRDC4 调节高血糖引起的心肌和骨骼肌毒性，揭示了将高血糖与心脏/骨骼肌病和运动不耐受联系起来的新分子框架。