Metabolic derangements are a major complication of severe burn injury and adversely affect the clinical outcome of burn patients. Severe metabolic derangement (aka burn cachexia) is recognized by concomitant hyperlactatemia, hypermetabolism, insulin resistance, and muscle wasting. For years, the predominant assumption has been that insulin resistance drives the development of these metabolic derangements, although the underlying mechanism has never been identified. The currently prescribed insulin-sensitizers (i.e., metformin, thiazolidinediones) produce adverse side effects (e.g., lactic acidosis, edema) in burn patients and therefore new insulin-sensitizers have been awaited. Despite decades of research, however, no new treatments that target stress-induced insulin resistance or metabolic dysfunction have emerged. Hence, new strategies need to be developed. A recent study points to 'protein farnesylation' as a promising new target, but further study is required to clarify the underlying molecular mechanism(s). This study showed that burn increases protein farnesylation and that farnesyltransfrase (FTase) inhibitor (FTI) reverses burn-induced muscle insulin resistance. The explanation for this new concept of burn insulin resistance is the Warburg effect (aka cytopathic hypoxia). The Warburg effect was originally described as the metabolic reprogramming of cancer cells in favor of glycolytic ATP synthesis as opposed to mitochondrial oxidative phosphorylation, even under normoxia. Recently, the Warburg effect has been linked to the inflammatory response, and it has been widely observed in various inflammatory diseases, including critical illness. Preliminary studies showed that burn causes the Warburg effect in mouse muscle as indicated by the induction of hypoxia-inducible factor-1? (HIF-1?) and pyruvate kinase isoform M2 (PKM2), a hallmark of the Warburg effect, as well as by increased aerobic glycolysis under normoxic conditions, all of which can be reversed by FTI. The data in cultured muscle cells also indicated that: (1) HIF-1? expression is sufficient and required for cytokine-induced insulin resistance; and (2) farnesylation of LKB1 (a master kinase in the regulation of metabolism) mediates cytokine- induced HIF-1? expression. Based on these recent studies and preliminary data it is hypothesized that the Warburg effect causes and/or exacerbates insulin resistance in skeletal muscle, which challenges the existing paradigm.
Aim 1 will test the hypothesis that the burn-induced Warburg effect causes and/or exacerbates insulin resistance in mice.
Aim 2 will determine whether pharmacological and genetic inhibition of protein farnesylation reverses or ameliorates the Warburg effect and insulin resistance.
Aim 3 will test the hypothesis that farnesylation of LKB1 mediates the burn-induced Warburg effect and muscle insulin resistance in mice. This project is designed to determine whether the Warburg effect is an appropriate target for reversing burn-induced insulin resistance and metabolic disturbance. This research is expected to provide the scientific basis for a clinical trial of tipifarnib, a farnesyltransferase inhibitor (FTI), in burn patients.
Metabolic alterations are a major complication of severe burn injury and interfere with wound healing and recovery of burn patients. These metabolic alterations include elevated blood glucose and lactic acid levels, and muscle wasting. The proposed studies will test the effectiveness of using a drug called as farnesylation inhibitor (used in cancer treatment) to reverse metabolic dysfunction induced by burn injury in mice. The data will be used to judge the merit of pursuing clinical testing for this treatment in burn patiens.
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| Nakazawa, Harumasa; Ikeda, Kazuhiro; Shinozaki, Shohei et al. (2017) Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1? and mTORC1: Role of protein farnesylation. Sci Rep 7:6618 |
| Nakazawa, Harumasa; Chang, Kyungho; Shinozaki, Shohei et al. (2017) iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-?B and p53. PLoS One 12:e0170391 |
