The important functional change in skeletal muscle following thermal injury is muscle weakness, which is associated with loss of muscle mass (atrophy) resulting in hypoventilation, difficulty in weaning off respirators, and decreased mobilization. A recognized pathway for accelerated muscle protein breakdown is the activation of ubiquitin-proteosome system. Apoptosis or programmed cell death is a relatively recently described mechanism of loss of parenchymal tissue and can be initiated by many factors, including growth factor withdrawal. Recent studies following burn injury have confirmed apoptotic changes in skeletal muscles. Insulin is a key growth factor, which, via downstream Akt/PKB signaling pathway, plays a key role in protein synthesis, mitochondrial function, and anti-apoptosis. Insulin resistance with decreased signaling via PI3-K/AktJPKB pathway, is a concomitant feature of burns. The hypothesis tested is that the decreased growth factor (insulin) signaling, specifically via Akt/PKB leads to apoptotic changes in muscle with mitochondria playing a central role. It is also postulated that the burn injury results in the activation of inducible nitric oxide synthase (iNOS) with release of reactive nitric oxide (NO), which alters Akt/PKB by post translational modifications. Thus, the proposed studies, using muscle cell cultures, and rodents with thermal injury, will critically evaluate the role of NO in decreased Akt/PKB activation, mitochondrial function, and in the apoptotic changes seen in muscle. The hypothesis that burn-induced mitochondrial, apoptotic and functional (tension) changes in muscle can be attenuated by either infection/over-expression of constitutively active Akt/PKB, highly specific iNOS inhibitors, or by inhibition of pro-apoptotic caspases will also be tested. The proposed studies, using morphologic, biochemical and molecular pharmacological approaches, together with functional (tension studies), and protein kinetic analyses would characterize the effects of burn injury on local and distant muscle apoptosis, and their relationship to neuromuscular dysfunction. Our studies on the effectiveness of iNOS inhibitor, and use of iNOS knockout mice, and the use of caspase inhibitors will thus provide significant insights into the pathogenesis of muscle wasting, and furnish novel therapeutic armamentaria and/or strategies to treat burn-induced neuromuscular dysfunction in humans. Information obtained from these mechanistic studies will provide a scientific basis and rationale for therapeutic maneuvers to prevent and/or rectify neuromuscular complications of burns in humans.
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