Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH.
Diabetes and Metabolism Research Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.
Diabetes. 2020 May;69(5):1052-1064. doi: 10.2337/db19-0807. Epub 2020 Mar 5.
MG53 is a member of the TRIM protein family that is predominantly expressed in striated muscles and participates in cell membrane repair. Controversy exists regarding MG53's role in insulin signaling and manifestation of diabetes. We generated mice with either whole-body ablation or sustained elevation of MG53 in the bloodstream in order to evaluate the physiological function of MG53 in diabetes. To quantify the amount of MG53 protein in circulation, we developed a monoclonal antibody against MG53 with high specificity. Western blot using this antibody revealed lower or no change of serum MG53 levels in mice or patients with diabetes compared with control subjects. Neither whole-body ablation of MG53 nor sustained elevation of MG53 in circulation altered insulin signaling and glucose handling in mice. Instead, mice with ablation of MG53 were more susceptible to streptozotocin-induced dysfunctional handling of glucose compared with the wild-type littermates. Alkaline-induced corneal injury demonstrated delayed healing in mice, which was restored by topical administration of recombinant human (rh)MG53. Daily intravenous administration of rhMG53 in rats at concentrations up to 10 mg/kg did not produce adverse effects on glucose handling. These findings challenge the hypothetical function of MG53 as a causative factor for the development of diabetes. Our data suggest that rhMG53 is a potentially safe and effective biologic to treat diabetic oculopathy in rodents.
肌球蛋白重链结合蛋白 53（MG53）是 TRIM 蛋白家族的成员，主要在横纹肌中表达，并参与细胞膜修复。MG53 在胰岛素信号转导和糖尿病发病机制中的作用存在争议。我们生成了全身性敲除或持续升高血液中 MG53 的 小鼠，以评估 MG53 在糖尿病中的生理功能。为了定量检测循环中 MG53 蛋白的含量，我们开发了一种针对 MG53 的高特异性单克隆抗体。使用该抗体进行 Western blot 分析显示，与对照组相比，糖尿病 小鼠或患者的血清 MG53 水平降低或无变化。全身性敲除 MG53 或持续升高血液中 MG53 水平均未改变 小鼠的胰岛素信号转导和葡萄糖代谢。相反，与野生型同窝仔相比，MG53 敲除的小鼠更容易发生链脲佐菌素诱导的葡萄糖代谢功能障碍。碱性诱导的角膜损伤显示 小鼠的愈合延迟，而局部给予重组人（rh）MG53 可恢复其愈合。在大鼠中，以高达 10mg/kg 的浓度每日静脉内给予 rhMG53 不会对葡萄糖代谢产生不良影响。这些发现挑战了 MG53 作为糖尿病发展的致病因素的假设功能。我们的数据表明，rhMG53 是一种潜在安全有效的生物制剂，可用于治疗啮齿动物的糖尿病性眼病变。
