title: Upregulation of MG53 induces diabetic cardiomyopathy through transcriptional activation of peroxisome proliferation-activated receptor α.
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.
  
  
  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.
authors: 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.
authors: Fenghua
authors: F
authors: Liu
authors: 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.
authors: Ruisheng
authors: R
authors: Song
authors: 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.
authors: Yuanqing
authors: Y
authors: Feng
authors: 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.
authors: Jiaojiao
authors: J
authors: Guo
authors: 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.
authors: Yanmin
authors: Y
authors: Chen
authors: 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.
authors: Yong
authors: Y
authors: Zhang
authors: 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.
authors: Tao
authors: T
authors: Chen
authors: 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.
authors: Yanru
authors: Y
authors: Wang
authors: 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.
authors: Yanyi
authors: Y
authors: Huang
authors: 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.
authors: Chuan-Yun
authors: CY
authors: Li
authors: 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.
authors: Chunmei
authors: C
authors: Cao
authors: 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.
authors: Yan
authors: Y
authors: Zhang
authors: 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. xiaor@pku.edu.cn huxxx025@pku.edu.cn.
authors: Xinli
authors: X
authors: Hu
authors: 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. xiaor@pku.edu.cn huxxx025@pku.edu.cn.
authors: Rui-ping
authors: RP
authors: Xiao
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D058065:Diabetic Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005813:Genes, Synthetic; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics* / Q000502:physiology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D047493:PPAR alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C538824:MG53 protein, mouse; D008565:Membrane Proteins; D047493:PPAR alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D011972:Receptor, Insulin; D018995:Myosin Heavy Chains
keywords: MG53 protein, mouse; diabetic cardiomyopathies; insulin resistance; peroxisome proliferation-activated receptors