Burn-induced loss of muscle mass and decrease in tension generating capacity, due to the nitrogen catabolic state, increases morbidity and mortality. The goals ofthis proposal in mice are to delineate the cellular and molecular mechanisms of muscle wasting, and pharmacologically prevent the catabolic state of burns. In view ofthe heterogeneous effects of burn on diverse signaling pathways, a multi-pronged approach to modulate the manifold effects of burn on muscle metabolism is proposed. This approach will be achieved by the Specific Aims, which test three hypotheses:
Specific Aim 1 : (a) that burn-injury-induced activation of GSK-3b leads to mitochondrial dysfunction, decreased anabolic signaling, and muscle wasting;(b) that GSK- 3b inhibitor (SB216373) will correct these aberrations and ameliorate muscle wasting of burns.
Specific Aim 2 : (a) that SIRTI deacetylase function is depressed following burns resulting in decreased insulin signaling and mitochondrial dysfunction;(b) that an activator of SIRTI function (SRT1720) will enhance anabolic signaling and mitochondrial function resulting in maintenance of muscle mass.
Specific Aim 3 : (a) that burn injury induces increased protein famesylation leading to decreased anabolic signaling via Akt/PKB and mitochondrial dysfunction resulting in muscle wasting;(b) Inhibition of famesylation (statin, or FTI-277) will attenuate activation of Ras (a major target of farnesylation)-JNK pathway and reverse anabolic signaling aberrations and mitochondrial dysfunction and thereby prevent muscle mass loss. The studies proposed combine in vivo physiology, molecular pharmacology, and genetic techniques, together with correctional therapeutics and gene chip microarrays, which together will provide snapshots of functional genomics, and advance our knowledge of organizimal pathophysiology and function at multiple levels from genes to proteins, from cellular responses to organ (whole muscle) function. This integrated approach will delineate some of the pathways involved in muscle wasting of burns and use untested therapeutic measures to correct the aberrant signaling changes that lead to muscle wasting in mice. These studies would provide scientific rationale for pharmacologic maneuvers to prevent muscle wasting in humans following burns.
The results of the proposed studies will not only provide novel mechanistic insights in muscle wasting of burns, but also use untested strategies to rectify the muscle wasting after burn injury. The results from these studies, when applied to patients, will help improve the clinical complications associated with loss of muscle mass and muscle function.
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