An MG53-IRS1-interaction disruptor ameliorates insulin resistance

다국어 초록 (Multilingual Abstract)

Mitsugumin 53 (MG53) is an E3 ligase that induces insulin receptor substrate-1 (IRS-1) ubiquitination and degradation in skeletal muscle. We previously demonstrated that the pharmaceutical disruption of the MG53-IRS-1 interaction improves insulin sensitivity by abrogating IRS-1 ubiquitination and increasing IRS-1 levels in C2C12 myotubes. Here, we developed a novel MG53-IRS-1 interaction disruptor (MID-00935) that ameliorates insulin resistance in diet-induced obese (DIO) mice. MID-00935 disrupted the molecular interaction of MG53 and IRS-1, abrogated MG53-induced IRS-1 ubiquitination and degradation and improved insulin signaling in C2C12 myotubes. Oral administration of MID-00935 increased insulin-induced IRS-1, Akt, and Erk phosphorylation via increasing IRS-1 levels in the skeletal muscle of DIO mice. In DIO mice, MID-00935 treatment lowered fasting blood glucose levels and improved glucose disposal in glucose and insulin tolerance tests. These results suggest that MID-00935 may be a potential muscle-targeting drug candidate for treating insulin resistance.

참고문헌 (Reference)

1 Simona Ognjanovic, "Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975-2005" Wiley 115 (115): 4218-4226, 2009

2 Yanlin Jia, "Treatment of acute lung injury by targeting MG53-mediated cell membrane repair" Springer Nature 5 (5): 2014

3 C E Quinn, "Thiazolidinediones: effects on insulin resistance and the cardiovascular system" Wiley 153 (153): 636-645, 2008

4 Derek M. Erion, "The role of lipids in the pathogenesis and treatment of type 2 diabetes and associated co-morbidities" 생화학분자생물학회 49 (49): 139-148, 2016

5 D. Thiebaud, "The Effect of Graded Doses of Insulin on Total Glucose Uptake, Glucose Oxidation, and Glucose Storage in Man" American Diabetes Association 31 (31): 957-963, 1982

6 Soon-Young Jung, "TRIM72, a novel negative feedback regulator of myogenesis, is transcriptionally activated by the synergism of MyoD (or myogenin) and MEF2" Elsevier BV 396 (396): 238-245, 2010

7 C S Lee, "TRIM72 negatively regulates myogenesis via targeting insulin receptor substrate-1" Springer Nature 17 (17): 1254-1265, 2010

8 Shingo Nemoto, "Relationships among protein tyrosine phosphatase 1B, angiotensin II, and insulin-mediated aortic responses in type 2 diabetic Goto–Kakizaki rats" Elsevier BV 233 (233): 64-71, 2014

9 M J Saad, "Regulation of insulin receptor substrate-1 in liver and muscle of animal models of insulin resistance." American Society for Clinical Investigation 90 (90): 1839-1849, 1992

10 Mandarino, L. J., "Regulation of hexokinase II and glycogen synthase mRNA, protein, and activity in human muscle" 269 : E701-E708, 1995

11 Knowler, W. C., "Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin" Massachusetts Medical Society 346 (346): 393-403, 2002

12 Weisleder, N., "Recombinant MG53 protein modulates therapeutic cell membrane repair in treatment of muscular dystrophy" 4 : 139ra185-, 2012

13 Laura J. Berman, "Physical activity is related to insulin sensitivity in children and adolescents, independent of adiposity: a review of the literature" Wiley 28 (28): 395-408, 2012

14 Abd A. Tahrani, "Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus" Springer Nature 12 (12): 566-592, 2016

15 Chia-Hsuin Chang, "Oral Insulin Secretagogues, Insulin, and Cancer Risk in Type 2 Diabetes Mellitus" The Endocrine Society 97 (97): E1170-E1175, 2012

16 홍진, "Myosin heavy chain is stabilized by BCL-2 interacting cell death suppressor (BIS) in skeletal muscle" 생화학분자생물학회 48 : 1-9, 2016

17 Andrew W. Norris, "Muscle-specific PPARγ-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones" American Society for Clinical Investigation 112 (112): 608-618, 2003

18 CHRISTIAN K. ROBERTS, "Modification of Insulin Sensitivity and Glycemic Control by Activity and Exercise" Ovid Technologies (Wolters Kluwer Health) 45 (45): 1868-1877, 2013

19 Nga Nguyen, "Mitsugumin 53 (MG53) Ligase Ubiquitinates Focal Adhesion Kinase during Skeletal Myogenesis" American Society for Biochemistry & Molecular Biology (ASBMB) 289 (289): 3209-3216, 2014

20 이현, "Mitochondrial oxidative phosphorylation complexes exist in the sarcolemma of skeletal muscle" 생화학분자생물학회 49 (49): 116-121, 2016

21 N. Musi, "Metformin Increases AMP-Activated Protein Kinase Activity in Skeletal Muscle of Subjects With Type 2 Diabetes" American Diabetes Association 51 (51): 2074-2081, 2002

22 Bart Wessels, "Metformin Impairs Mitochondrial Function in Skeletal Muscle of Both Lean and Diabetic Rats in a Dose-Dependent Manner" Public Library of Science (PLoS) 9 (9): e100525-, 2014

23 Chuanxi Cai, "Membrane Repair Defects in Muscular Dystrophy Are Linked to Altered Interaction between MG53, Caveolin-3, and Dysferlin" American Society for Biochemistry & Molecular Biology (ASBMB) 284 (284): 15894-15902, 2009

24 Duann, P., "MG53-mediated cell membrane repair protects against acute kidney injury" 7 : 279ra236-, 2015

25 Jae-Sung Yi, "MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling" Springer Nature 4 (4): 2013

26 Hyun Lee, "MG53-IRS-1 (Mitsugumin 53-Insulin Receptor Substrate-1) Interaction Disruptor Sensitizes Insulin Signaling in Skeletal Muscle" American Society for Biochemistry & Molecular Biology (ASBMB) 291 (291): 26627-26635, 2016

27 Yao, Y., "MG53 permeates through blood-brain barrier to protect ischemic brain injury" 7 : 22474-22485, 2016

28 Chuanxi Cai, "MG53 nucleates assembly of cell membrane repair machinery" Springer Nature 11 (11): 56-64, 2009

29 Weifeng Yao, "MG53 anchored by dysferlin to cell membrane reduces hepatocyte apoptosis which induced by ischaemia/reperfusion injury in vivo and in vitro" Wiley 21 (21): 2503-2513, 2017

30 Lemckert, F. A., "Lack of MG53 in human heart precludes utility as a biomarker of myocardial injury or endogenous cardioprotective factor" 110 : 178-187, 2016

31 Hiroyuki Tamemoto, "Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1" Springer Nature 372 (372): 182-186, 1994

32 C. M. Rondinone, "Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus" Proceedings of the National Academy of Sciences 94 (94): 4171-4175, 1997

33 L J Goodyear, "Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects." American Society for Clinical Investigation 95 (95): 2195-2204, 1995

34 Hyun Lee, "Extracellular reactive oxygen species are generated by a plasma membrane oxidative phosphorylation system" Elsevier BV 112 : 504-514, 2017

35 Bo He, "Enhancing Muscle Membrane Repair by Gene Delivery of MG53 Ameliorates Muscular Dystrophy and Heart Failure in δ-Sarcoglycan-deficient Hamsters" Elsevier BV 20 (20): 727-735, 2012

36 R A DeFronzo, "Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus." American Society for Clinical Investigation 76 (76): 149-155, 1985

37 Yu, Q., "Effective glycaemic control critically determines insulin cardioprotection against ischaemia/reperfusion injury in anaesthetized dogs" 103 : 238-247, 2014

38 Benjamin T. Corona, "Effect of recombinant human MG53 protein on tourniquet-induced ischemia-reperfusion injury in rat muscle" Wiley 49 (49): 919-921, 2014

39 Tao Tan, "Dual function of MG53 in membrane repair and insulin signaling" 생화학분자생물학회 49 (49): 414-423, 2016

40 N J Kerouz, "Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse." American Society for Clinical Investigation 100 (100): 3164-3172, 1997

41 Ruisheng Song, "Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders" Springer Nature 494 (494): 375-379, 2013

42 Benoit Viollet, "Cellular and molecular mechanisms of metformin: an overview" Portland Press Ltd. 122 (122): 253-270, 2012

43 Jianxun Liu, "Cardioprotection of recombinant human MG53 protein in a porcine model of ischemia and reperfusion injury" Elsevier BV 80 : 10-19, 2015

44 Eiichi Araki, "Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene" Springer Nature 372 (372): 186-190, 1994