MG53 E3 Ligase-Dead Mutant Protects Diabetic Hearts From Acute Ischemic/Reperfusion Injury and Ameliorates Diet-Induced Cardiometabolic Damage

• Published in: Diabetes (New York, N.Y.) Vol. 71; no. 2; pp. 298 - 314
• Main Authors: Feng, Han, Shen, Hao, Robeson, Matthew J, Wu, Yue-Han, Wu, Hong-Kun, Chen, Geng-Jia, Zhang, Shuo, Xie, Peng, Jin, Li, He, Yanyun, Wang, Yingfan, Lv, Fengxiang, Hu, Xinli, Zhang, Yan, Xiao, Rui-Ping
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.02.2022
• Subjects: Animals; Cardiomyopathy; Cells, Cultured; Complications; Cytoprotection - genetics; Diabetes; Diabetes mellitus; Diabetic Cardiomyopathies - complications; Diabetic Cardiomyopathies - genetics; Diabetic Cardiomyopathies - metabolism; Diabetic Cardiomyopathies - physiopathology; Diet, High-Fat; Female; Heart; Heart - physiopathology; High fat diet; Humans; Hyperglycemia; Ischemia; Male; Membrane Proteins - genetics; Metabolic disorders; Metabolic Syndrome - genetics; Metabolic Syndrome - metabolism; Metabolic Syndrome - pathology; Metabolic Syndrome - physiopathology; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Mortality; Mutants; Myocardial infarction; Myocardial Reperfusion Injury - etiology; Myocardial Reperfusion Injury - prevention & control; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - physiology; Reperfusion; Side effects; Signal Transduction - genetics; Ubiquitin-protein ligase
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db21-0322

Cardiometabolic diseases, including diabetes and its cardiovascular complications, are the global leading causes of death, highlighting a major unmet medical need. Over the past decade, mitsugumin 53 (MG53), also called TRIM72, has emerged as a powerful agent for myocardial membrane repair and cardioprotection, but its therapeutic value is complicated by its E3 ligase activity, which mediates metabolic disorders. Here, we show that an E3 ligase-dead mutant, MG53-C14A, retains its cardioprotective function without causing metabolic adverse effects. When administered in normal animals, both the recombinant human wild-type MG53 protein (rhMG53-WT) and its E3 ligase-dead mutant (rhMG53-C14A) protected the heart equally from myocardial infarction and ischemia/reperfusion (I/R) injury. However, in diabetic db/db mice, rhMG53-WT treatment markedly aggravated hyperglycemia, cardiac I/R injury, and mortality, whereas acute and chronic treatment with rhMG53-C14A still effectively ameliorated I/R-induced myocardial injury and mortality or diabetic cardiomyopathy, respectively, without metabolic adverse effects. Furthermore, knock-in of MG53-C14A protected the mice from high-fat diet-induced metabolic disorders and cardiac damage. Thus, the E3 ligase-dead mutant MG53-C14A not only protects the heart from acute myocardial injury but also counteracts metabolic stress, providing a potentially important therapy for the treatment of acute myocardial injury in metabolic disorders, including diabetes and obesity.