MuRF1-dependent regulation of systemic carbohydrate metabolism as revealed from transgenic mouse studies

J Mol Biol. 2008 Jun 13;379(4):666-77. doi: 10.1016/j.jmb.2008.03.049. Epub 2008 Apr 3.

Abstract

Under various pathophysiological muscle-wasting conditions, such as diabetes and starvation, a family of ubiquitin ligases, including muscle-specific RING-finger protein 1 (MuRF1), are induced to target muscle proteins for degradation via ubiquitination. We have generated transgenic mouse lines over-expressing MuRF1 in a skeletal muscle-specific fashion (MuRF1-TG mice) in an attempt to identify the in vivo targets of MuRF1. MuRF1-TG lines were viable, had normal fertility and normal muscle weights at eight weeks of age. Comparison of quadriceps from MuRF1-TG and wild type mice did not reveal elevated multi-ubiquitination of myosin as observed in human patients with muscle wasting. Instead, MuRF1-TG mice expressed lower levels of pyruvate dehydrogenase (PDH), a mitochondrial key enzyme in charge of glycolysis, and of its regulator PDK2. Furthermore, yeast two-hybrid interaction studies demonstrated the interaction of MuRF1 with PDH, PDK2, PDK4, PKM2 (all participating in glycolysis) and with phosphorylase beta (PYGM) and glycogenin (both regulating glycogen metabolism). Consistent with the idea that MuRF1 may regulate carbohydrate metabolism, MuRF1-TG mice had twofold elevated insulin blood levels and lower hepatic glycogen contents. To further examine MuRF1's role for systemic carbohydrate regulation, we performed glucose tolerance tests (GTT) in wild type and MuRF1-TG mice. During GTT, MuRF1-TG mice developed striking hyperinsulinaemia and hepatic glycogen stores, that were depleted at basal levels, became rapidly replenished. Taken together, our data demonstrate that MuRF1 expression in skeletal muscle re-directs glycogen synthesis to the liver and stimulates pancreatic insulin secretion, thereby providing a regulatory feedback loop that connects skeletal muscle metabolism with the liver and the pancreas during metabolic stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Carbohydrate Metabolism*
  • DNA Primers / genetics
  • Gene Expression
  • Gene Expression Profiling
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Liver / metabolism
  • Liver Glycogen / metabolism
  • Mice
  • Mice, Transgenic
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / metabolism
  • Muscular Atrophy / etiology
  • Muscular Atrophy / metabolism
  • Proteome
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Tissue Distribution
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • DNA Primers
  • Insulin
  • Liver Glycogen
  • Muscle Proteins
  • Proteome
  • Recombinant Proteins
  • Tripartite Motif Proteins
  • TRIM63 protein, human
  • Ubiquitin-Protein Ligases

Associated data

  • GEO/GSE10626