Upregulation of MG53 induces diabetic cardiomyopathy through transcriptional activation of peroxisome proliferation-activated receptor α.

Abstract

Diabetic cardiomyopathy, which contributes to >50% diabetic death, is featured by myocardial lipid accumulation, hypertrophy, fibrosis, and cardiac dysfunction. The mechanism underlying diabetic cardiomyopathy is poorly understood. Recent studies have shown that a striated muscle-specific E3 ligase Mitsugumin 53 (MG53, or TRIM72) constitutes a primary causal factor of systemic insulin resistance and metabolic disorders. Although it is most abundantly expressed in myocardium, the biological and pathological roles of MG53 in triggering cardiac metabolic disorders remain elusive. Here we show that cardiac-specific transgenic expression of MG53 induces diabetic cardiomyopathy in mice. Specifically, MG53 transgenic mouse develops severe diabetic cardiomyopathy at 20 weeks of age, as manifested by insulin resistance, compromised glucose uptake, increased lipid accumulation, myocardial hypertrophy, fibrosis, and cardiac dysfunction. Overexpression of MG53 leads to insulin resistant via destabilizing insulin receptor and insulin receptor substrate 1. More importantly, we identified a novel role of MG53 in transcriptional upregulation of peroxisome proliferation-activated receptor alpha and its target genes, resulting in lipid accumulation and lipid toxicity, thereby contributing to diabetic cardiomyopathy. Our results suggest that overexpression of myocardial MG53 is sufficient to induce diabetic cardiomyopathy via dual mechanisms involving upregulation of peroxisome proliferation-activated receptor alpha and impairment of insulin signaling. These findings not only reveal a novel function of MG53 in regulating cardiac peroxisome proliferation-activated receptor alpha gene expression and lipid metabolism, but also underscore MG53 as an important therapeutic target for diabetes mellitus and associated cardiomyopathy.