Nakayama Yoshinobu, Kobayashi Satoru, Masihuddin Aliya, Abdali Syed Amir, Seneviratne A M Pramodh Bandara, Ishii Sachiyo, Iida Jun, Liang Qiangrong, Yoshioka Jun
Department of Molecular, Cellular and Biomedical Sciences, City University of New York School of Medicine, City College of New York, New York, NY (Y.N., A.M., S.A.A.,A.M.P.B.S., J.Y.).
Department of Anesthesiology and Intensive Care, Kindai University Faculty of Medicine, Osaka, Japan (Y.N.).
Circ Res. 2024 Jul 19;135(3):416-433. doi: 10.1161/CIRCRESAHA.123.323158. Epub 2024 Jul 1.
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.
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.
High glucose promoted translocation of MondoA into the nucleus, which upregulated transcriptional expression, increased lysosomal GLUT1 trafficking, and blocked glucose transport in cardiomyocytes, forming a feedback mechanism. This role of was confirmed in human muscular cells from type 2 diabetic patients. Prolonged hyperglycemia upregulated myocardial 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 augmented tissue glucose transport and mitochondrial respiration, protecting the heart and muscle from tissue damage. Stress hemodynamic analysis and treadmill exhaustion test uncovered that -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 have the potential to contribute to exercise intolerance by interfering with cardiac metabolism through its interaction with GLUT1 in diabetes. Importantly, the mutation mouse line exhibited greater exercise tolerance, showing the potential therapeutic impact on diabetic cardiomyopathy by disrupting the interaction between ARRDC4 and GLUT1.
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.
运动不耐受是糖尿病患者预后不良的独立预测因素。高血糖与运动不耐受之间关联的潜在机制尚不清楚。我们最近证明，含 arrestin 结构域蛋白 4（ARRDC4）与葡萄糖转运蛋白 1（GLUT1）之间的相互作用调节心脏代谢。
为了确定该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 在糖尿病性心脏/骨骼肌病发病机制中的作用。
高糖促进 MondoA 易位至细胞核，上调转录表达，增加溶酶体 GLUT1 转运，并阻断心肌细胞中的葡萄糖转运，形成一种反馈机制。这一作用在 2 型糖尿病患者的人类肌肉细胞中得到证实。在多种糖尿病小鼠模型中，长期高血糖上调心肌 ARRDC4 表达。我们分析了胰岛素缺乏小鼠中高血糖诱导的心脏和骨骼肌异常。高血糖增加晚期糖基化终产物，并引发氧化应激和内质网应激，导致心脏和外周肌肉细胞凋亡。敲除 ARRDC4 可增强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步机耐力试验发现，在糖尿病状态下，ARRDC4 基因敲除小鼠比野生型动物具有更大的心脏变力/变时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心脏特异性过表达表明，在糖尿病中，高水平的心肌 ARRDC4 可能通过与 GLUT1 相互作用干扰心脏代谢进而导致运动不耐受。重要的是，ARRDC4 突变小鼠品系表现出更高的运动耐受性，表明破坏 ARRDC4 与 GLUT1 之间的相互作用对糖尿病性心肌病具有潜在治疗作用。
ARRDC4 调节高血糖对心脏和骨骼肌的毒性作用，揭示了一个将高血糖与心脏/骨骼肌病及运动不耐受联系起来的新分子框架。
