Burn-induced muscle mass loss and decrease in tension generating capacity, due to the nitrogen catabolic state, increase morbidity and mortality. The goals of this proposal are to identify novel potential molecular targets and apply untested pharmacological approaches to prevent the catabolic state and muscle wasting in burns in mice. In view of the heterogeneous effects of burn on diverse signaling pathways, an integrated 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-3beta leads to muscle wasting mainly by suppressing beta-catenin pathway;(b) that GSK-3|3 inhibitor (SB216763) will correct these aberrations and ameliorate muscle wasting of burns.
Specific Aim 2 : that SIRTI deacetylase function is depressed in muscle following burns, as reflected by increased acetylation of p53, NF-KBeta and PGC-1 a, contributing to mitochondria-mediated apoptotic changes and enhanced inflammatory response, and subsequent muscle wasting, all of which will be mitigated by SIRTI activator (SRT1720).
Specific Aim 3 : that burn injury induces increased protein farnesylation leading to activation of the Ras (a major target of farnesylation)-JNK pathway, and decreased anabolic signaling via the IRS-1-Akt pathway;(b) that inhibition of farnesylation by statin or FTI-277 will reverse these alterations and thereby prevent muscle mass loss in burns. The proposed studies combine in vivo muscle physiology, molecular pharmacology and genetic approaches (using muscle-specific knockout mice for GSK-3BETA, SIRTI and farnesyltransferase), together with genome-wide gene expression and transcriptome analyses. This will advance our knowledge of organismal pathophysiology and function at multiple levels from genes to proteins, from cellular responses to organ (whole muscle) function, and of cross talks between signaling pathways mediated by GSK-3beta, SIRTI and farnesylation in muscle metabolic dysregulation in burns. This project is designed to determine whether inhibitors/activator for GSK-3BETA, SIRTI, and farnesyltransferase are novel potential strategies to reverse muscle wasting and metabolic derangements in burn patients.
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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