Mortality from prolonged critical illness, including recovery from burn injury, remains high at least in part because of unchecked muscle catabolism that is difficult to prevent by nutrient supplementation alone. Despite adequate treatment of the underlying injury, this metabolic dysregulation can persist for months and contribute significantly to fatal complications. Intensive insulin therapy to restore euglycemia can reduce mortality and morbidity, but long-term insulin therapy can be difficult to implement safely. Thus, the elaboration of mechanistic-based strategies to modulate burn injury induced insulin resistance in skeletal muscle and liver is clinically important. The molecular basis of burn-induced insulin resistance is complex and involves dysregulation of both intracellular signaling and inter-tissue metabolism. Recently, we showed that mice lacking skeletal muscle Irsi and Irs2 display severe muscle catabolism. Whether the dysregulation of Irsi and Irs2 predisposes muscle to burn induced insulin resistance will be established in this project. In SA1, we will investigate the function of Irsi and Irs2 in skeletal muscle after burn injury using mice lacking, alternatively, Irs2 (MK02-mice) or Irsi (MKOI-mice). The potential for derepressed FoxOI or 3 transcriptional activity to cause muscle catabolism after burn injury in these genetically modified mice will be established via muscle specific knockout of FoxOI or 3 in MK02- or MKOI-mice. In SA2, we will investigate the functional significance of Irsi S/T-phosphorylation profiles in skeletal muscle following burn injury. Using our unique library of antibodies directed against specific phosphoserine sites of lrs1/2 together with Luminex detection technology, we will identify changes in the global and dynamic S/T-phosphorylation of Irsi that occurs after burns, including their relation to the metabolically important binding of PI-3Kto Irsi. The results obtained in mouse models will be compared directly with human skeletal muscle samples. In SA3, we will establish whether the phosphorylation of S307(lrs1) and S302(lrs1) regulates insulin signaling cascades in mice during burn injury. These experiments will be conducted using A307(lrs1) or A302(lrs1) knockin mice intercrossed with M0K2-mice, so that the results are uncomplicated by Irs2 signaling.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM021700-33
Application #
8668969
Study Section
Special Emphasis Panel (ZGM1-PPBC-5)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
33
Fiscal Year
2014
Total Cost
$373,205
Indirect Cost
$5,189
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Shank, Erik S; Martyn, Jeevendra A; Donelan, Mathias B et al. (2016) Ultrasound-Guided Regional Anesthesia for Pediatric Burn Reconstructive Surgery: A Prospective Study. J Burn Care Res 37:e213-7
Ueki, Ryusuke; Liu, Li; Kashiwagi, Shizuka et al. (2016) Role of Elevated Fibrinogen in Burn-Induced Mitochondrial Dysfunction: Protective Effects of Glycyrrhizin. Shock 46:382-9
Copps, Kyle D; Hançer, Nancy J; Qiu, Wei et al. (2016) Serine 302 Phosphorylation of Mouse Insulin Receptor Substrate 1 (IRS1) Is Dispensable for Normal Insulin Signaling and Feedback Regulation by Hepatic S6 Kinase. J Biol Chem 291:8602-17
Frydman, Galit H; Bendapudi, Pavan K; Marini, Robert P et al. (2016) Coagulation Biomarkers in Healthy Chinese-Origin Rhesus Macaques (Macaca mulatta). J Am Assoc Lab Anim Sci 55:252-9
Agarwal, Shailesh; Loder, Shawn; Brownley, Cameron et al. (2016) Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification. Proc Natl Acad Sci U S A 113:E338-47
Tompkins, Ronald G (2015) Survival from burns in the new millennium: 70 years' experience from a single institution. Ann Surg 261:263-8
Nakazawa, Harumasa; Yamada, Marina; Tanaka, Tomokazu et al. (2015) Role of protein farnesylation in burn-induced metabolic derangements and insulin resistance in mouse skeletal muscle. PLoS One 10:e0116633
Bittner, Edward A; Shank, Erik; Woodson, Lee et al. (2015) Acute and perioperative care of the burn-injured patient. Anesthesiology 122:448-64
Kashiwagi, Aki; Hosokawa, Sachiko; Maeyama, Yoshihiro et al. (2015) Anesthesia with Disuse Leads to Autophagy Up-regulation in the Skeletal Muscle. Anesthesiology 122:1075-83
White, Morris F (2015) Longevity: Mapping the path to a longer life. Nature 524:170-1

Showing the most recent 10 out of 102 publications