Cardiac Muscle Protein Catabolism in Diabetes Mellitus: Activation of the Ubiquitin-Proteasome System by Insulin Deficiency

Endocrinology. 2008 Nov;149(11):5384-90. doi: 10.1210/en.2008-0132. Epub 2008 Jul 24.

Abstract

Protein degradation is increased by both insulin deficiency and insulin resistance in humans and animal models. In skeletal muscle this insulin-dependent increase in protein degradation involves activation of both caspase-3 and the ubiquitin-proteasome system. The influence of abnormal insulin signaling on protein metabolism in cardiac muscle is not well understood; therefore, we measured protein degradation in cardiac muscle of mice with streptozotocin-induced diabetes. Insulin deficiency increased both total muscle proteolysis (measured as tyrosine release in muscle slices or extracts) and the degradation of the myofibrillar protein actin (measured as the appearance of a 14-kDa actin fragment). Expression of ubiquitin mRNA and chymotrypsin-like activity in the proteasome were increased, indicating activation of the ubiquitin-proteasome system in diabetic mouse heart. We also evaluated possible signaling pathways that might regulate cardiac muscle proteolysis. Insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and Akt phosphorylation were decreased. Insulin replacement prevented the decrease in IRS-1/Akt phosphorylation, the increase in proteolysis, and attenuated the increase in ubiquitin mRNA. We conclude that insulinopenia accelerates proteolysis in cardiac muscle by reducing IRS-1/Akt signaling, which leads to activation of the ubiquitin-proteasome proteolytic pathway.

Publication types

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

MeSH terms

  • Animals
  • Caspases / metabolism
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / pathology
  • Enzyme Activation / drug effects
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • Insulin / deficiency*
  • Insulin / pharmacology
  • Insulin Receptor Substrate Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Oncogene Protein v-akt / metabolism
  • Oncogene Protein v-akt / physiology
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Processing, Post-Translational / drug effects
  • Protein Processing, Post-Translational / physiology
  • Streptozocin
  • Ubiquitin / metabolism*

Substances

  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Muscle Proteins
  • Ubiquitin
  • Streptozocin
  • Oncogene Protein v-akt
  • Caspases
  • Proteasome Endopeptidase Complex