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.
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.
|Zhao, Gaofeng; Yu, Yong-Ming; Kaneki, Masao et al. (2015) Simvastatin reduces burn injury-induced splenic apoptosis via downregulation of the TNF-?/NF-?B pathway. Ann Surg 261:1006-12|
|Watada, Susumu; Yu, Yong-Ming; Fischman, Alan J et al. (2014) Evaluation of intragastric vs intraperitoneal glucose tolerance tests in the evaluation of insulin resistance in a rodent model of burn injury and glucagon-like polypeptide-1 treatment. J Burn Care Res 35:e66-72|
|Zhao, Gaofeng; Yu, Yong-Ming; Shoup, Timothy M et al. (2014) Membrane potential-dependent uptake of 18F-triphenylphosphonium--a new voltage sensor as an imaging agent for detecting burn-induced apoptosis. J Surg Res 188:473-9|
|Carter, Edward A; Paul, Kasie; Bonab, Ali A et al. (2014) Effect of exercise on burn-induced changes in tissue-specific glucose metabolism. J Burn Care Res 35:470-3|
|Lee, Sangseok; Yang, Hong-Seuk; Sasakawa, Tomoki et al. (2014) Immobilization with atrophy induces de novo expression of neuronal nicotinic *7 acetylcholine receptors in muscle contributing to neurotransmission. Anesthesiology 120:76-85|
|Fu, Glenn K; Xu, Weihong; Wilhelmy, Julie et al. (2014) Molecular indexing enables quantitative targeted RNA sequencing and reveals poor efficiencies in standard library preparations. Proc Natl Acad Sci U S A 111:1891-6|
|Khan, Mohammed A S; Sahani, Nita; Neville, Kevin A et al. (2014) Nonsurgically induced disuse muscle atrophy and neuromuscular dysfunction upregulates alpha7 acetylcholine receptors. Can J Physiol Pharmacol 92:1-8|
|Ueda, Masashi; Iwasaki, Hajime; Wang, Shuxing et al. (2014) Cannabinoid receptor type 1 antagonist, AM251, attenuates mechanical allodynia and thermal hyperalgesia after burn injury. Anesthesiology 121:1311-9|
|Ibrahim, Amir; Fagan, Shawn; Keaney, Tim et al. (2014) A simple cost-saving measure: 2.5% mafenide acetate solution. J Burn Care Res 35:349-53|
|Shank, Erik S; Martyn, Jeevendra A; Donelan, Mathias B et al. (2014) Ultrasound-Guided Regional Anesthesia for Pediatric Burn Reconstructive Surgery: A Prospective Study. J Burn Care Res :|
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