A novel cellular defect in diabetes: membrane repair failure.
A novel cellular defect in diabetes: membrane repair failure.
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作者：
Howard AC;McNeil AK;Xiong F;Xiong WC;McNeil PL
骨骼肌肌病是一种常见的糖尿病并发症。肌病的一个可能原因是肌细胞无法修复收缩产生的质膜损伤。在这里，我们测试的假设，糖尿病诱导骨骼肌肌细胞修复缺陷。用激光和染料摄取共聚焦成像来损伤来自1型（INS 2秋田+/-）和2型（db/db）糖尿病小鼠的完整肌肉中的肌细胞，以测试修复效率。还评估了糖尿病小鼠在下坡跑后的膜修复缺陷，其在体内诱导肌细胞质膜破裂损伤。细胞培养模型被用来研究晚期糖基化终产物（AGEs）和AGE受体（AGEs）在这种修复缺陷发展中的作用。糖尿病心肌细胞显示激光损伤后比对照组显着更多的染料流入，表明修复缺陷。下坡跑也导致糖尿病小鼠更高水平的修复失败。这种修复缺陷在培养的细胞中通过长时间暴露于高葡萄糖来模拟。AGE形成的抑制消除了这种葡萄糖诱导的修复缺陷。然而，修复缺陷可以诱导，在没有高葡萄糖，通过增强AGE结合到β-内酰胺酶，或简单地通过增加细胞暴露于AGE。由于修复失败的一个后果是快速细胞死亡（通过坏死），我们的证明，修复失败的糖尿病提出了一个新的机制，肌病发展的糖尿病。
Skeletal muscle myopathy is a common diabetes complication. One possible cause of myopathy is myocyte failure to repair contraction-generated plasma membrane injuries. Here, we test the hypothesis that diabetes induces a repair defect in skeletal muscle myocytes. Myocytes in intact muscle from type 1 (INS2Akita+/−) and type 2 (db/db) diabetic mice were injured with a laser and dye uptake imaged confocally to test repair efficiency. Membrane repair defects were also assessed in diabetic mice after downhill running, which induces myocyte plasma membrane disruption injuries in vivo. A cell culture model was used to investigate the role of advanced glycation end products (AGEs) and the receptor for AGE (RAGE) in development of this repair defect. Diabetic myocytes displayed significantly more dye influx after laser injury than controls, indicating a repair deficiency. Downhill running also resulted in a higher level of repair failure in diabetic mice. This repair defect was mimicked in cultured cells by prolonged exposure to high glucose. Inhibition of the formation of AGE eliminated this glucose-induced repair defect. However, a repair defect could be induced, in the absence of high glucose, by enhancing AGE binding to RAGE, or simply by increasing cell exposure to AGE. Because one consequence of repair failure is rapid cell death (via necrosis), our demonstration that repair fails in diabetes suggests a new mechanism by which myopathy develops in diabetes.
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