title: Insulin-like growth factor-1 restores dexamethasone-induced heart growth arrest in rats: the role of the ubiquitin pathway.
abstract: OBJECTIVE
  In skeletal muscle, glucocorticoids induce catabolism and proteolysis which is accomplished via the ubiquitin (Ub) proteolytic pathway. Cardiac muscle is a striated muscle which, compared to skeletal muscle, more abundantly expresses components of the Ub pathway, thus suggesting an important role for this pathway in heart physiology. The aim of our study was to explore the role of the Ub pathway in heart muscle physiology.
  
  
  METHODS
  We treated rats for three days with a pharmacologic dose of dexamethasone (DEXA) 0.5mg/100g body weight (BW). An attempt was also made to counteract the DEXA effect by co-treatment with insulin-like growth factor-1 (IGF-1; 0.35 mg/100g BW).
  
  
  RESULTS
  DEXA treatment caused a 7.8% decrease in heart weight compared to control (p<0.05) and also increased heart tissue levels of the ubiquitin-conjugating enzyme E2 and the 20S proteasome protein. Myofibrillar proteins degraded by the ubiquitin pathway (α-actin, myoglobin, and troponin 1) were all decreased by DEXA, while ubiquitinated forms of α-actin were increased. Co-treatment with IGF-1 completely prevented DEXA-induced decrease in heart weight, an effect which was accompanied by decreased heart tissue levels of several ubiquitinated proteins including α-actin, the 20S proteasome protein, E2-14 kDa mRNA, and C-3 proteasome subunit mRNA, while the levels of non-ubiquinated α-actin, myoglobin, and troponin 1 were all partially restored.
  
  
  CONCLUSIONS
  These results demonstrate that DEXA activates the ubiquitin proteolytic pathway in the heart and that IGF-1 efficiently counteracts this effect. Our findings reveal a possible mechanism for the anti-proteolytic actions of IGF-1 and its cardioprotective role involving the Ub pathway.
authors.affiliation: Department of Pediatrics, Division of Endocrinology, Medical School, University of Patras, Greece. dchrysis@upatras.gr
authors.forename: Dionisios
authors.initials: D
authors.lastname: Chrysis
authors.forename: Andrei
authors.initials: A
authors.lastname: Chagin
authors.forename: Lars
authors.initials: L
authors.lastname: Sävendahl
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D003907:Dexamethasone / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D004353:Drug Evaluation, Preclinical; D006321:Heart / Q000187:drug effects* / Q000254:growth & development*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D002316:Cardiotonic Agents; D012333:RNA, Messenger; D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D046988:Proteasome Endopeptidase Complex