Amelioration of ischemia‐reperfusion–induced muscle injury by the recombinant human MG53 protein

Zhu, Hua; Hou, Jincai; Roe, Janet L.; Park, Ki Ho; Tan, Tao; Zheng, Yongri; Li, Lei; Zhang, Cuixiang; Liu, Jianxun; Liu, Zhenguo; Ma, Jianjie; Walters, James

doi:10.1002/mus.24619

Cited by 33 publications

(45 citation statements)

References 32 publications

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“…Intriguing evidence suggests that MG53, a cytosolic TRIM family E3 ubiquitin ligase involved in muscle fiber wound repair, might also function extracellularly. Recent studies reported a marked improvement in acute injury animal models by intravenous injections of recombinant MG53 [73–75], suggesting that its mechanism of action may not require that the protein enter cells and join the cytosolic vesicular “patch” repair machinery, as originally proposed [60]. …”

Section: Look Outside: a Role For Extracellularly Released Proteinmentioning

confidence: 99%

Above the fray: Surface remodeling by secreted lysosomal enzymes leads to endocytosis-mediated plasma membrane repair

Andrews

Corrotte

Castro-Gomes

2015

Seminars in Cell & Developmental Biology

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The study of plasma membrane repair is coming of age. Mirroring human adolescence, the field shows at the same time signs of maturity and significant uncertainty, confusion and skepticism. Here we discuss concepts that emerged from experimental data over the years, some of which are solidly established while others are still subject to different interpretations. The firmly established concepts include the critical requirement for Ca2+ in wound repair, and the role of rapid exocytosis of intracellular vesicles. Lysosomes are being increasingly recognized as the major vesicles involved in injury-induced exocytosis in many cell types, as a growing number of laboratories detect markers for these organelles on the cell surface and lysosomal hydrolases in the supernatant of wounded cells. The more recent observation of massive endocytosis following Ca2+-triggered exocytosis initially came as a surprise, but this finding is also being increasingly reported by different groups, shifting the discussion to the mechanisms by which endocytosis promotes repair, and whether it operates or not in parallel with the shedding of membrane blebs. We discuss how the abundant intracellular vesicles that undergo homotypic fusion close to wound sites, previously interpreted as exocytic membrane patches, actually acquire extracellular tracers demonstrating their endocytic origin. We also suggest that an initial, temporary patch that prevents cyto-sol loss until the bilayer is restored might result not from vesicular fusion, but from rapid Ca2+-dependent crosslinking and aggregation of cytosolic proteins. Finally, we propose that cell surface remodeling, orchestrated by the extracellular release of lysosomal hydrolases and perhaps also cytosolic molecules, may represent a key aspect of the plasma membrane repair mechanism that has received little attention so far.

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Section: Look Outside: a Role For Extracellularly Released Proteinmentioning

confidence: 99%

Above the fray: Surface remodeling by secreted lysosomal enzymes leads to endocytosis-mediated plasma membrane repair

Andrews

Corrotte

Castro-Gomes

2015

Seminars in Cell & Developmental Biology

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“…We previously identified a protein, mitsugumin 53 (MG53), as a main component for plasma membrane repair machinery (5). An extensive series of subsequent studies established that recombinant human (rh)MG53 protein can be used to treat injuries to multiple organs, including skeletal muscle, heart, lung, kidney, brain, cornea, and skin (6)(7)(8)(9)(10)(11)(12)(13). Many of these organs are also impacted by long-standing diabetes, suggesting that MG53 may be an ideal therapeutic agent for treating multiorgan damage in diabetes.…”

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confidence: 99%

MG53 Does Not Manifest the Development of Diabetes in db/db Mice

et al. 2020

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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 db/db 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 db/db mice or patients with diabetes compared with control subjects. Neither wholebody ablation of MG53 nor sustained elevation of MG53 in circulation altered insulin signaling and glucose handling in db/db 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 db/db 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.

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“…Developing a TRIM72 augmentation therapy for the treatment of tissue injurious diseases had been a continuing research area of interest. Recombinant TRIM72 protein was shown to have notably therapeutic effects in mouse models of muscular dystrophy (90,273) and for ischemic reperfusion injury in muscle and heart (49,152,291). Because striated muscles have the highest levels of endogenous TRIM72 expression in mice, it is not clear why the abundant repair protein is not sufficient to rescue tissue injuries, since there were no mutations or polymorphisms of TRIM72 identified so far in tissue injurious diseases.…”

Section: Repair Mechanisms For Injured Lung Cellsmentioning

confidence: 99%

Plasma membrane wounding and repair in pulmonary diseases

Cong

Hubmayr

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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Various pathophysiological conditions such as surfactant dysfunction, mechanical ventilation, inflammation, pathogen products, environmental exposures, and gastric acid aspiration stress lung cells, and the compromise of plasma membranes occurs as a result. The mechanisms necessary for cells to repair plasma membrane defects have been extensively investigated in the last two decades, and some of these key repair mechanisms are also shown to occur following lung cell injury. Because it was theorized that lung wounding and repair are involved in the pathogenesis of acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF), in this review, we summarized the experimental evidence of lung cell injury in these two devastating syndromes and discuss relevant genetic, physical, and biological injury mechanisms, as well as mechanisms used by lung cells for cell survival and membrane repair. Finally, we discuss relevant signaling pathways that may be activated by chronic or repeated lung cell injury as an extension of our cell injury and repair focus in this review. We hope that a holistic view of injurious stimuli relevant for ARDS and IPF could lead to updated experimental models. In addition, parallel discussion of membrane repair mechanisms in lung cells and injury-activated signaling pathways would encourage research to bridge gaps in current knowledge. Indeed, deep understanding of lung cell wounding and repair, and discovery of relevant repair moieties for lung cells, should inspire the development of new therapies that are likely preventive and broadly effective for targeting injurious pulmonary diseases.

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Amelioration of ischemia‐reperfusion–induced muscle injury by the recombinant human MG53 protein

Cited by 33 publications

References 32 publications

Above the fray: Surface remodeling by secreted lysosomal enzymes leads to endocytosis-mediated plasma membrane repair

Above the fray: Surface remodeling by secreted lysosomal enzymes leads to endocytosis-mediated plasma membrane repair

MG53 Does Not Manifest the Development of Diabetes in db/db Mice

Plasma membrane wounding and repair in pulmonary diseases

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