Upregulation of MG53 Induces Diabetic Cardiomyopathy Through Transcriptional Activation of Peroxisome Proliferation-Activated Receptor α

Author:

Liu Fenghua1,Song Ruisheng1,Feng Yuanqing1,Guo Jiaojiao1,Chen Yanmin1,Zhang Yong1,Chen Tao1,Wang Yanru1,Huang Yanyi1,Li Chuan-Yun1,Cao Chunmei1,Zhang Yan1,Hu Xinli1,Xiao Rui-ping1

Affiliation:

1. From Institute of Molecular Medicine (F.L., R.S., Y.F., J.G., Y.Z., Y.W., C.L., C.C., Y.Z., X.H., R.X.), State Key Laboratory of Biomembrane and Membrane Biotechnology (F.L., R.S., Y.F., J.G., Y.C., Y.Z., Y.W., C.C., Y.Z., X.H., R.X.), Biodynamic Optical Imaging Center (T.C., Y.H.), Center for Life Sciences (Y.C., C.L., R.X.), and Beijing City Key Laboratory of Cardiometabolic Molecular Medicine (R.X.), Peking University, Beijing, China.

Abstract

Background— 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. Methods and Results— 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. Conclusions— 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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