Metabolic disturbances remain a significant cause of morbidity and mortality of burn patients, despite advancements in the resuscitation and surgical treatment. These aberrations include hypermetabolism, protein catabolism, aberrant fuel preference (predominant oxidafion of fatty acid over glucose), and muscle wasting. Insulin resistance has been postulated as a key player in burn-induced metabolic derangements. Conversely, metabolic derangements have been proposed as an inducer and/or enhancer of insulin resistance, as well. The IRS-1-Akt-Fox01/3 pathway plays a central role in metabolic acfions of insulin in skeletal muscle. Activation of Fox01/3 promotes protein degradation and muscle wasting, and inhibits glucose oxidation in skeletal muscle. In addition to attenuated Akt activity, FoxO transcription factors are activated by MST1 protein kinase and O-glycosylation. The preliminary data in skeletal muscle of burn patients and burned rodents indicate that: (1) IRS-1 expression is suppressed, while the expression of PTP- 1B, a negative regulator of insulin signaling, is increased;(2) serine phosphorylation of IRS-1 is increased: and (3) activities of FoxOI/3 and expression ofthe target genes of FoxOs are increased along with decreased Akt activity and increased stimulatory signals (MST1 activity, O-glycosylation). Based on previous studies and our solid preliminary data, we hypothesize that activation of FoxOI/3, which results from attenuated Akt activity, increased MST1 activity, and O-glycosylation, plays an important role in burn injuryinduced metabolic derangements, and that FoxOs-mediated metabolic disturbances contribute to exacerbafion of impaired IRS-l-mediated insulin signaling in skeletal muscle after burn injury.
Specific Aim 1 will establish attenuated IRS-1-mediated signaling, and clarify serine/threonine phosphorylation status of IRS-1 in muscle of burn patients.
Specific Aim 2 will determine the role of FoxOI and Fox03 in metabolic derangements, specifically muscle wasting and oxidation of glucose versus fatty acid, and in impaired IRS-1- Akt signaling in muscle of burn patients and burned mice, using muscle-specific FoxOI or Fox03 knockout mice.
Specific Aim 3 will determine the safety and efficacy of antisense morpholino oligomers (PMOs) targeting PTP-1 B, FoxOI, and Fox03 in burned mice. Rhesus monkeys, and burn patients. This project is designed to determine whether PTP-1 B, FoxOI, and Fox03 are clinically relevant molecular targets to reverse insulin resistance and metabolic disturbances in burn patients. The proposed studies are expected to develop a new antisense PMO-based therapeutic strategy to improve the outcome of burn patients.

Public Health Relevance

Metabolic disturbances remain a signficant cause of morbidity and mortality in burn patients. New knowledge gained in this project should promote potential new genomic-based therapeutics to reduce the complications associated with dysregulated metabolism in burn patients.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-SRC-5 (TB))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
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