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MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling.

ABSTRACT: Mitsugumin 53 (MG53) negatively regulates skeletal myogenesis by targeting insulin receptor substrate 1 (IRS-1). Here, we show that MG53 is an ubiquitin E3 ligase that induces IRS-1 ubiquitination with the help of an E2-conjugating enzyme, UBE2H. Molecular manipulations that disrupt the E3-ligase function of MG53 abolish IRS-1 ubiquitination and enhance skeletal myogenesis. Skeletal muscles derived from the MG53-/- mice show an elevated IRS-1 level with enhanced insulin signalling, which protects the MG53-/- mice from developing insulin resistance when challenged with a high-fat/high-sucrose diet. Muscle samples derived from human diabetic patients and mice with insulin resistance show normal expression of MG53, indicating that altered MG53 expression does not serve as a causative factor for the development of metabolic disorders. Thus, therapeutic interventions that target the interaction between MG53 and IRS-1 may be a novel approach for the treatment of metabolic diseases that are associated with insulin resistance.

SUBMITTER: Yi JS

PROVIDER: S-EPMC3941707 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling.

Yi Jae-Sung JS Park Jun Sub JS Ham Young-Mi YM Nguyen Nga N Lee Na-Rae NR Hong Jin J Kim Bong-Woo BW Lee Hyun H Lee Chang-Seok CS Jeong Byung-Cheon BC Song Hyun Kyu HK Cho Hana H Kim Yoon Ki YK Lee Jae-Seon JS Park Kyong Soo KS Shin Haksub H Choi Inho I Lee Seung Hee SH Park Woo Jin WJ Park Shi-Young SY Choi Cheol Soo CS Lin Peihui P Karunasiri Malith M Tan Tao T Duann Pu P Zhu Hua H Ma Jianjie J Ko Young-Gyu YG

Nature communications 20130101

Mitsugumin 53 (MG53) negatively regulates skeletal myogenesis by targeting insulin receptor substrate 1 (IRS-1). Here, we show that MG53 is an ubiquitin E3 ligase that induces IRS-1 ubiquitination with the help of an E2-conjugating enzyme, UBE2H. Molecular manipulations that disrupt the E3-ligase function of MG53 abolish IRS-1 ubiquitination and enhance skeletal myogenesis. Skeletal muscles derived from the MG53-/- mice show an elevated IRS-1 level with enhanced insulin signalling, which protect ...[more]

PMID: 23965929

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Project description:ObjectiveTo explore the possible mechanism of electroacupuncture to improve insulin sensitivity in type 2 diabetes rats.MethodsFourteen Zucker Diabetic Fatty (ZDF) rats were randomly divided into two groups: a model group and an electroacupuncture group, with 7 rats in each group. Seven Zucker Lean (ZL) rats served as a control group. All rats were fed with Purina #5008 for 4 weeks, and the electroacupuncture group received 4-week electroacupuncture intervention, while the control group and model group received no intervention. We measured fasting blood glucose (FBG) on the fourth weekend. After 4 weeks of intervention, the expression levels of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, IRS-1 serine/threonine phosphorylation, and GLUT4 in quadriceps femoris muscles were detected by western Blot.ResultsCompared with the model group, the electroacupuncture group had a lower level of fasting blood glucose, serum insulin level, and insulin resistance index (P < 0.05). The electroacupuncture group had lower IRS-1 serine/threonine phosphorylation than the model group, with the difference showing statistical significance (P < 0.05). Furthermore, the mean score (MS) of the control group showed the lowest phosphorylation expression, followed by the electroacupuncture group, while the model group had the highest level of phosphorylated protein expression. The level of IRS-1 tyrosine phosphorylation at Tyr895 sites was compared, and the result showed that there was no significant difference between the electroacupuncture group and the control group (P > 0.05), and the electroacupuncture group had higher phosphorylation expression than the model group (P < 0.05). Compared with the control group and the model group, the expression level of GLUT4 protein in the electroacupuncture group was significantly increased (P < 0.05).ConclusionElectroacupuncture has the effect to improve the insulin sensitivity of type 2 diabetic ZDF rats by reducing fasting blood glucose, insulin level, and insulin resistance index, effectively up regulating the expression of GLUT4 protein in quadriceps femoris muscle. The mechanism is related to the regulation of skeletal muscle IRS-1 serine/threonine and tyrosine phosphorylation levels.

Dataset Information

MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling.

Publications

MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling.

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