Author: Ren, Hongmei ; Shi, Yu ; Gong, Xue ; Yang, Peili ; Cai, Qi ; Wu, Gengze ; Guo, Xinyi ; Tian, Miao ; Chen, Yinghong ; Tan, Wenjie ; Zeng, Chunyu ; Ma, Jianjie

INTRODUCTIONSeptic cardiac dysfunction (SCD) is the most common complication of sepsis, which has become the primary cause of death in intensive care units. The muscle-specific protein mitsugumin-53 (MG53) has been identified to protect cell integrity as a "Molecular Band-Aid".OBJECTIVESThe recombinant human MG53 (rhMG53) pretreatment has been reported to prevent cardiac function damage caused by cecal ligation and puncture (CLP). However, whether or not MG53 protects against SCD remains to be further clarified.METHODSC57BL/6J mice were intraperitoneally injected with lipopolysaccharide (LPS) to generate the SCD model. MG53 was overexpressed by intravenously injected adeno-associated virus, and the rhMG53 was administrated intraperitoneally. The cardiac function was evaluated by echocardiography, and the cardiac inflammation was assessed through ELISA and Western blot. The mechanisms of MG53 were studied by quantitative real-time PCR (qPCR) and co-immunoprecipitation (co-IP).RESULTSOur present study found that MG53 expression was lower in hearts from SCD mice than controls. Overexpression or exogenous MG53 treatment alleviated cardiac dysfunction, improved survival rate in SCD mice, accompanied with improved pathological changes, reduced cardiomyocyte apoptosis, and lowered inflammatory factor levels in serum or hearts. Mechanistically, MG53 inhibited TLR4 transcriptional activity by ubiquitinating ATF2, an essential transcriptional factor for TLR4, which ultimately reduced the expression of TLR4.CONCLUSIONMG53 protect the cardiac function against sepsis by down-regulation of TLR4 expression, via ubiquitination of ATF2, a TLR4 transcriptional factor, which might be a promising therapeutic approach for septic cardiac dysfunction.

01 Feb 2025·Diabetes

Friend or Foe: The Paradoxical Roles of MG53 in Diabetes

Review

Author: Yuan, Shuangshuang ; Luo, Mao ; Yu, Qin ; Wang, Liqun ; Wu, Jianbo

MG53 is predominantly expressed in striated muscles. The role of MG53 in diabetes has gradually been 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 insulin receptor 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, findings have been reported from other studies 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 article, 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.

01 Feb 2025·Journal of Cellular and Molecular Medicine

Mitsugumin 53 Inhibits Angiogenesis Through Regulating Focal Adhesion Turnover and Tip Cell Formation

Article

Author: Li, Yongjie ; Li, Tian ; Chen, Tangting ; Lv, Hongbin ; Luo, Mao ; Wang, Liqun ; Li, Rong ; Zheng, Youkun ; Wu, Jianbo ; Chen, Ni ; Liu, Yan ; Yuan, Shuangshuang ; You, Jingcan ; Yu, Qin ; Deng, Xin

ABSTRACTOur previous studies have identified mitsugumin 53 (MG53) as a novel regulator for angiogenesis by directly entering endothelial cells and modulating focal adhesion kinase (FAK) activation, but little is known about how rhMG53 is taken up by cells and how rhMG53 mediates cell movement. In the present study, we demonstrated that the knockdown of caveolin‐1 and the clathrin inhibitor, pitstop‐2, both significantly reduced the entry of rhMG53 into endothelial cells, indicating caveolae‐dependent and clathrin‐dependent endocytosis during this process. The internalised rhMG53 remarkably inhibited the phosphorylation of FAK and the downstream signalling molecule paxillin, consequently resulting in a significant decrease in focal adhesion turnover during endothelial cell spreading and migration. Using a 3D collagen culture model, we further found that rhMG53 significantly inhibited tip cell formation and tubulogenesis. Furthermore, rhMG53 also remarkably prevented alkaline injury‐induced corneal neovascularization in vivo. Taken together, these results indicate that rhMG53 inhibits angiogenesis through regulating focal adhesion turnover and tip cell formation. This may elucidate novel molecular mechanisms involved in rhMG53 uptake and rhMG53‐modulated endothelial cell function and provide evidence for the potential utility of rhMG53 in treating diseases with excessive angiogenesis.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Kidney Injury	Preclinical	United States	The Ohio State University	18 Mar 2015

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