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

Nat Commun. 2013;4:2354. doi: 10.1038/ncomms3354.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Differentiation
  • Cell Line
  • Diabetes Mellitus / metabolism
  • Diet, High-Fat
  • Glucose Tolerance Test
  • Insulin / metabolism*
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism*
  • Insulin Resistance
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Development / genetics*
  • Muscle, Skeletal / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitination

Substances

  • Carrier Proteins
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • MG53 protein, mouse
  • Membrane Proteins
  • RNA, Small Interfering
  • Ubiquitin-Conjugating Enzymes