MG53 is predominantly expressed in striated muscles. The role of MG53 in diabetes mellitus has been gradually elucidated but is still full of controversy. Some reports have indicated that MG53 is upregulated in animal models with metabolic disorders, and that muscle-specific MG53 upregulation is sufficient to induce whole-body insulin resistance and metabolic syndrome through targeting both the insulin receptor (IR) and IR substrate-1 (IRS-1) for ubiquitin-dependent degradation. Additionally, MG53 has been identified as a myokine/cardiokine that is secreted from striated muscles into the bloodstream and circulating MG53 has further been shown to trigger insulin resistance by binding to the extracellular domain of the IR, thereby allosterically inhibiting insulin signaling. Conversely, other studies have reported findings that contradict these results. Specifically, no significant change in MG53 expression in striated muscles or serum has been observed in diabetic models, and the MG53-mediated degradation of IRS-1 may be insufficient to induce insulin resistance due to the compensatory roles of other IRS subtypes. Furthermore, sustained elevation of MG53 levels in serum or systemic administration of recombinant human MG53 (rhMG53) has shown no impact on metabolic function. In this review, we will fully characterize these two disparate views, strive to provide critical insights into their contrasts and propose several specific experimental approaches that may yield additional evidence. Our goal is to encourage the scientific community to elucidate the effects of MG53 on metabolic diseases and the molecular mechanisms involved, thereby providing the theoretical basis for the treatment of metabolic diseases and the applications of rhMG53.

中文翻译：

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朋友或敌人：MG53 在糖尿病中的悖论作用


MG53 主要在横纹肌中表达。MG53 在糖尿病中的作用已逐渐阐明，但仍充满争议。一些报告表明，MG53 在代谢紊乱的动物模型中上调，肌肉特异性 MG53 上调足以通过靶向胰岛素受体 （IR） 和 IR 底物-1 （IRS-1） 进行泛素依赖性降解来诱导全身胰岛素抵抗和代谢综合征。此外，MG53 已被确定为从横纹肌分泌到血液中的肌因子/有氧因子，循环 MG53 进一步被证明通过与 IR 的细胞外结构域结合来触发胰岛素抵抗，从而变构抑制胰岛素信号传导。相反，其他研究报告了与这些结果相矛盾的结果。具体来说，在糖尿病模型中未观察到横纹肌或血清中 MG53 表达的显着变化，并且由于其他 IRS 亚型的代偿作用，MG53 介导的 IRS-1 降解可能不足以诱导胰岛素抵抗。此外，血清中 MG53 水平的持续升高或重组人 MG53 （rhMG53） 的全身给药对代谢功能没有影响。在这篇综述中，我们将全面描述这两种不同的观点，努力为它们的对比提供批判性的见解，并提出几种可能产生额外证据的具体实验方法。我们的目标是鼓励科学界阐明 MG53 对代谢疾病的影响及其所涉及的分子机制，从而为 rhMG53 的代谢疾病治疗和应用提供理论依据。