Insulin resistance is a key component of multiple metabolic derangements, which include hypermetabolism, hyperglycemia, increased catabolism, a shift from carbohydrate to fatty acid oxidation, and muscle wasting in burn injury. We have previously shown that impaired IRSI-mediated insuliri signaling occurs after burn injury in skeletal muscle. Reduced expression and increased S/T phosphorylation of IRSI are involved in skeletal muscle insulin resistance of burned mice. After burn injury, expression of protein tyrosine phosphatase-1 B (PTP-1B), which is a negative regulator of insulin receptor/IRSI-mediated signaling, is increased in muscle. FoxOI and 3 genes and their resultant proteins represent evolutionally conserved targets of insulin signaling and regulate metabolism in many tissues including skeletal muscle. Transcriptome analysis of the genomewide expression profile in burn patients indicates that transcriptional activity of FoxOI and 6 is increased in skeletal muscle after burn injury. mRNA expression of target genes of FoxOI and 3 is significantly greater in skeletal muscle of burn patients compared with healthy controls. Consistently, burn injury is associated with decreased phosphorylation of FoxOI and 3 at Akt target sites, and increases in O-glycosylation of FoxOI and MST1 activity in mouse muscle. Therefore, the hypothesis of this project is that IRSI-FoxO dysregulations are key contributors to many if not all of the metabolic derangements of.burn injury and that down-regulation and subsequent nuclear exclusion of FoxOs will improve or eliminate these effects. SA1 will establish the inhibitory effects of burn injury on IRSI-mediated signaling in human skeletal muscle of burn patients and healthy volunteers. SA2 will determine inhibitory and stimulatory phosphorylation, and Oglycosylation of FoxOI and 3 in burn patients and mice and the effects of derangements, insulin signaling, and alterations in gene expression profile in mouse skeletal muscle. SA3 will evaluate the safety and efficacy of PMO knockdown of FoxOI on insulin resistance in skeletal muscle in mice. Rhesus macaques, and healthy volunteers. This project will determine whether FoxOI PMO is a novel potential strategy to reverse insulin resistance and metabolic derangements in skeletal muscle in burn patients.
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.
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