title: The effect of insulin and exercise on c-Cbl protein abundance and phosphorylation in insulin-resistant skeletal muscle in lean and obese Zucker rats.
abstract: OBJECTIVE
  Recruitment of the protein c-Cbl to the insulin receptor (IR) and its tyrosine phosphorylation via a pathway that is independent from phosphatidylinositol 3'-kinase is necessary for insulin-stimulated GLUT4 translocation in 3T3-L1 adipocytes. The activation of this pathway by insulin or exercise has yet to be reported in skeletal muscle.
  
  
  METHODS
  Lean and obese Zucker rats were randomly assigned to one of three treatment groups: (i). control, (ii). insulin-stimulated or (iii). acute, exhaustive exercise. Hind limb skeletal muscle was removed and the phosphorylation state of IR, Akt and c-Cbl measured.
  
  
  RESULTS
  Insulin receptor phosphorylation was increased 12-fold after insulin stimulation ( p<0.0001) in lean rats and threefold in obese rats. Acute exercise had no effect on IR tyrosine phosphorylation. Similar results were found for serine phosphorylation of Akt. Exercise did not alter c-Cbl tyrosine phosphorylation in skeletal muscle of lean or obese rats. However, in contrast to previous studies in adipocytes, c-Cbl tyrosine phosphorylation was reduced after insulin treatment ( p<0.001).
  
  
  CONCLUSIONS
  We also found that c-Cbl associating protein expression is relatively low in skeletal muscle of Zucker rats compared to 3T3-L1 adipocytes and this could account for the reduced c-Cbl tyrosine phosphorylation after insulin treatment. Interestingly, basal levels of c-Cbl tyrosine phosphorylation were higher in skeletal muscle from insulin-resistant Zucker rats ( p<0.05), but the physiological relevance is not clear. We conclude that the regulation of c-Cbl phosphorylation in skeletal muscle differs from that previously reported in adipocytes.
authors.affiliation: School of Health Sciences, Deakin University, Burwood, Victoria, 3125, Australia.
authors.forename: G D
authors.initials: GD
authors.lastname: Wadley
authors.affiliation: School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia.
authors.forename: C R
authors.initials: CR
authors.lastname: Bruce
authors.affiliation: Health Sciences and Nutrition, Commonwealth Scientific and Industrial Research Organisation, Parkville, Victoria, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Konstantopoulos
authors.affiliation: Health Sciences and Nutrition, Commonwealth Scientific and Industrial Research Organisation, Parkville, Victoria, Australia.
authors.forename: S L
authors.initials: SL
authors.lastname: Macaulay
authors.affiliation: School of Health Sciences, Deakin University, Burwood, Victoria, 3125, Australia.
authors.forename: K F
authors.initials: KF
authors.lastname: Howlett
authors.affiliation: School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Hawley
authors.affiliation: School of Health Sciences, Deakin University, Burwood, Victoria, 3125, Australia. davidcs@deakin.edu.au.
authors.forename: D
authors.initials: D
authors.lastname: Cameron-Smith
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000503:physiopathology; D010766:Phosphorylation; D010805:Physical Conditioning, Animal; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D051381:Rats; D011924:Rats, Zucker; D013851:Thinness / Q000503:physiopathology; D044767:Ubiquitin-Protein Ligases / Q000187:drug effects / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; C495694:Slc2a4 protein, rat; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases