Molecular mechanism(s) of burn-induced insulin resistance in murine skeletal muscle: role of IRS phosphorylation.
Hyperglycemia, glucose intolerance and elevated insulin levels frequently occur in burned patients; however, the mechanism(s) for this insulin resistance has not been fully elucidated. One possible mechanism could involve alterations in the phosphorylation of serine 307 of the insulin receptor substrate-1 (IRS-1) via activation of stress kinase enzymes, including SAPK/JNK. In the present study we examined the time course of the effect of burn injury to mice on: levels of IRS-1 protein, phosphorylation of serine 307 of IRS-1, SAPK/JNK kinase levels and activity and Akt kinase activity in hind limb skeletal muscle. Burn injury produced a reduction in hind limb muscle mass 24 h after injury, and, which persisted for 168 h. At 24 h after injury, there was a dramatic ( approximately 9-fold) increase in phosphorylation of IRS-1 serine 307 followed by a more moderate elevation thereafter. Total IRS-1 protein was slightly elevated at 24 h after injury and decreased to levels below sham treated animals at the later times. Burn injury did not appear to change total SAPK/JNK protein content, however, enzyme activity was increased for 7 days after injury. Akt kinase activity was decreased in skeletal muscle following burn injury; providing a biochemical basis for burn-induced insulin resistance. These findings are consistent with the hypothesis that burn-induced insulin resistance may be related, at least in part, to alterations in the phosphorylation of key proteins in the insulin signaling cascade, including IRS-1, and that changes in stress kinases, such as SAPK/JNK produced by burn injury, may be responsible for these changes in phosphorylation.
Zhang
Qin
Q
Department of Surgery, Massachusetts General Hospital and Shriners Hospital for Children, Harvard Medical School, Boston, MA 02114, USA.
Carter
Edward A
EA
Ma
Bang-Yi
BY
White
Morris
M
Fischman
Alan J
AJ
Tompkins
Ronald G
RG
D000818:Animals; D002056:Burns / Q000150:complications* / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006614:Hindlimb / Q000166:cytology / Q000293:injuries / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D008297:Male; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000293:injuries / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction
D055504:Insulin Receptor Substrate Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; C526295:Irs1 protein, mouse