title: iNOS inhibitor, L-NIL, reverses burn-induced glycogen synthase kinase-3β activation in skeletal muscle of rats.
abstract: OBJECTIVE
  Recent studies suggest that activation of glycogen synthase kinase (GSK)-3β may be involved in burn injury-induced metabolic derangements and protein breakdown in skeletal muscle. However, the mechanism for GSK-3β activation after burn injury is unknown. To investigate the role of inducible nitric oxide synthase (iNOS) in this scenario, a major mediator of inflammation, we examined the effects of a specific inhibitor for iNOS, L-NIL, on GSK-3β activity in skeletal muscle of burned rats.
  
  
  METHODS
  Full-thickness third degree burn injury comprising 40% of total body surface area was produced under anesthesia in male Sprague-Dawley rats (160-190g) by immersing the back of the trunk for 15s and the abdomen for 8s in 80°C water. Burned and sham-burned rats were treated with L-NIL (60mg/kg BW, b.i.d., IP) or phosphate-buffered saline for three days. GSK-3β activity in skeletal muscle was evaluated by immune complex kinase assay, and by phosphorylation status of GSK-3β and its endogenous substrate, glycogen synthase.
  
  
  RESULTS
  GSK-3β activity was increased in a time-dependent manner in skeletal muscle after burn injury, concomitant with the induction of iNOS expression. iNOS inhibitor, L-NIL, reverted the elevated GSK-3β activity in skeletal muscle of burned rats, although L-NIL did not alter GSK-3β activity in sham-burned rats.
  
  
  CONCLUSIONS
  Our results clearly indicate that iNOS plays an important role in burn injury-induced GSK-3β activation in skeletal muscle. These findings suggest that iNOS may contribute to burn injury-induced metabolic derangements, in part, by activating GSK-3β.
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Boston, MA 02114, USA. mkaneki@helix.mgh.harvard.edu
authors.forename: Masao
authors.initials: M
authors.lastname: Kaneki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Fukushima
authors.forename: Shohei
authors.initials: S
authors.lastname: Shinozaki
authors.forename: Makiko
authors.initials: M
authors.lastname: Fukaya
authors.forename: Mayu
authors.initials: M
authors.lastname: Habiro
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shimizu
authors.forename: Kyungho
authors.initials: K
authors.lastname: Chang
authors.forename: Shingo
authors.initials: S
authors.lastname: Yasuhara
authors.forename: J A Jeevendra
authors.initials: JA
authors.lastname: Martyn
mesh_terms: D000818:Animals; D002056:Burns / Q000201:enzymology* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006006:Glycogen Synthase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology* / Q000293:injuries / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D052247:Nitric Oxide Synthase Type II; D006006:Glycogen Synthase; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D008239:Lysine