title: Role of protein farnesylation in burn-induced metabolic derangements and insulin resistance in mouse skeletal muscle.
abstract: OBJECTIVE
  Metabolic derangements, including insulin resistance and hyperlactatemia, are a major complication of major trauma (e.g., burn injury) and affect the prognosis of burn patients. Protein farnesylation, a posttranslational lipid modification of cysteine residues, has been emerging as a potential component of inflammatory response in sepsis. However, farnesylation has not yet been studied in major trauma. To study a role of farnesylation in burn-induced metabolic aberration, we examined the effects of farnesyltransferase (FTase) inhibitor, FTI-277, on burn-induced insulin resistance and metabolic alterations in mouse skeletal muscle.
  
  
  METHODS
  A full thickness burn (30% total body surface area) was produced under anesthesia in male C57BL/6 mice at 8 weeks of age. After the mice were treated with FTI-277 (5 mg/kg/day, IP) or vehicle for 3 days, muscle insulin signaling, metabolic alterations and inflammatory gene expression were evaluated.
  
  
  RESULTS
  Burn increased FTase expression and farnesylated proteins in mouse muscle compared with sham-burn at 3 days after burn. Simultaneously, insulin-stimulated phosphorylation of insulin receptor (IR), insulin receptor substrate (IRS)-1, Akt and GSK-3β was decreased. Protein expression of PTP-1B (a negative regulator of IR-IRS-1 signaling), PTEN (a negative regulator of Akt-mediated signaling), protein degradation and lactate release by muscle, and plasma lactate levels were increased by burn. Burn-induced impaired insulin signaling and metabolic dysfunction were associated with increased inflammatory gene expression. These burn-induced alterations were reversed or ameliorated by FTI-277.
  
  
  CONCLUSIONS
  Our data demonstrate that burn increased FTase expression and protein farnesylation along with insulin resistance, metabolic alterations and inflammatory response in mouse skeletal muscle, all of which were prevented by FTI-277 treatment. These results indicate that increased protein farnesylation plays a pivotal role in burn-induced metabolic dysfunction and inflammatory response. Our study identifies FTase as a novel potential molecular target to reverse or ameliorate metabolic derangements in burn patients.
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Harumasa
authors.initials: H
authors.lastname: Nakazawa
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America; Shriners Hospitals for Children, Boston, Massachusetts, United States of America.
authors.forename: Marina
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Kramer
authors.affiliation: Shriners Hospitals for Children, Boston, Massachusetts, United States of America; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Yong-Ming
authors.initials: YM
authors.lastname: Yu
authors.affiliation: Shriners Hospitals for Children, Boston, Massachusetts, United States of America.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Fischman
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America; Shriners Hospitals for Children, Boston, Massachusetts, United States of America.
authors.forename: J A Jeevendra
authors.initials: JA
authors.lastname: Martyn
authors.affiliation: Shriners Hospitals for Children, Boston, Massachusetts, United States of America; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tompkins
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America; Shriners Hospitals for Children, Boston, Massachusetts, United States of America.
authors.forename: Masao
authors.initials: M
authors.lastname: Kaneki
mesh_terms: D000818:Animals; D002056:Burns / Q000150:complications* / Q000378:metabolism*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*; D017368:Protein Prenylation
chemical_list: C096856:FTI 277; D008715:Methionine; D051231:Farnesyltranstransferase