Journal
DIABETES
Volume 71, Issue 2, Pages 298-314Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db21-0322
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Funding
- National Key R&D Program of China [2018YFA0507603, 2018YFA0800701, 2018YFA0800501]
- National Natural Science Foundation of China [31671177, 81630008, 81790621, 31970722, 31521062]
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The E3 ligase-dead mutant MG53-C14A, a variant of the mitsugumin 53 (MG53) protein, not only protects the heart from acute myocardial injury but also counteracts metabolic stress, making it a potentially important treatment for acute myocardial injury in metabolic disorders, including diabetes and obesity.
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.
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