Mortality from prolonged critical illness, including recovery from thermal trauma, remains high at least in part because of unchecked muscle catabolism that is difficult to prevent by nutrient supplementation alone. Despite adequate treatment ofthe underiying trauma, this metabolic dysregulafion can persist for months. Trauma-induced insulin resistance and hyperglycemia appear to impede recovery and contribute significanfiy to fatal complications. Project 3, "The molecular basis of burn-induced muscle insulin resistance" invesfigates the role of Irsl and lrs2 in murine skeletal muscle following thermal trauma. The experiments will elucidate the degree to which dysregulated Irsl and Irs2 signaling?especially the stress-induced serine and threonine phosphorylation of Irsl?mediates the persistent insulin resistance and protein wasting characterisfic of burn injury. The project focuses upon three Specific Aims: 1. Investigate the function of Irsl and lrs2 in skeletal muscle during thermal trauma. 2. Establish the relafion between mulfisite Ser/Thr-phosphorylafion of IRS1 and PI 3-kinase signaling during thermal injury. 3. Establish whether S307lrs1 or S302lrs1 phosphorylafion regulates insulin sensitivity during thermal injury.
The first Aim i nvestigates the effect of a 30% burn injury upon the Irsl and Irs2-branches ofthe insulin/IGF signaling cascade, by invesfigafing mice lacking, alternatively, Irs2 (MK02-mice) or Irsl (MKOI-mice) in the skeletal muscle to assess funcfion in the remaining branch ofthe signaling pathway. Whether derepressed FoxOI,3 transcripfional acfivity cause muscle catabolism following thermal trauma will also be determined by knockout of Foxol or Foxo3 in MK01- or MK02-mice.
The second Aim employs Luminex technology and unique phospho-site-specific monoclonal anfibodies against Irs1 to idenfify changes in the global and dynamic S/T-phosphorylafion of Irsl that occur following thermal trauma. Finally, the third Aim direcfiy invesfigates the role of two Irsl phosphorylafion sites, Ser307 or Ser302, in the modulafion of insulin sensifivity during thermal trauma. These experiments can reveal new mechanism-based strategies to enhance skeletal muscle insulin sensifivity that can restore nutrient flux to a level compatible with recovery from thermal trauma.
The proposed studies can reveal new ways to improve skeletal muscle insulin sensitivity after burn injury. Morever, this effort may provide novel insights applicable to the treatment of insulin resistance that promotes the metabolic syndrome and type 2 diabetes.
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