Recent work indicates that the intrinsic force-generating capacity and metabolic function of skeletal muscles are altered in patients with heart failure, and that skeletal muscle dysfunction contributes to fatigue and breathlessness in these patients. The underlying mechanism by which these myopathic changes occur in heart failure, however, is currently unknown. The purpose of the studies in this proposal is to test the hypothesis that some or all of the myopathic changes that develop in this condition are due to excessive myocyte generation of free radicals. We postulate that heart failure elicits an increase in myocyte phospholipase A2 (PLA2) activity levels, and that arachidonic acid generated by PLA2 interacts with the electron transport chain to augment free radical formation in resting and contracting muscle. We further propose that the radicals so produced react with and modify protein and lipid components of muscle which, in turn, alters muscle force generation and fatiguability. These hypotheses will be tested in three groups of experiments; in all studies a coronary ligation model will be used to produce heart failure in rats. The purpose of Objective I studies is to find evidence of heightened free radical formation by skeletal muscle in heart failure; experiments will measure both indices of free radical reaction with cellular constituents (i.e. lipid and protein oxidation products) and directly measure free radical formation by muscle using novel fluorescent techniques. Objective II studies will determine the cellular pathways responsible for free radical generation by skeletal myocytes in heart failure and, more specifically, determine if and by what process phospholipase A2 modulates muscle free radical generation in this condition. In Objective III, we will examine the role of free radicals in inducing muscle weakness and excessive fatiguability by determining if administration of free radical scavengers to heart failure animals preserves normal muscle function. Our preliminary studies provide the first evidence that excessive skeletal muscle free radical generation in heart failure is linked to reductions in muscle force-generating capacity in this condition. These data suggest that the proposed experiments should provide important information regarding the pathogenesis of heart failure-related skeletal muscle dysfunction.
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| Supinski, G S; Vanags, J; Callahan, L A (2009) Effect of proteasome inhibitors on endotoxin-induced diaphragm dysfunction. Am J Physiol Lung Cell Mol Physiol 296:L994-L1001 |
| Supinski, G S; Murphy, M P; Callahan, L A (2009) MitoQ administration prevents endotoxin-induced cardiac dysfunction. Am J Physiol Regul Integr Comp Physiol 297:R1095-102 |
| Callahan, Leigh Ann; Supinski, Gerald S (2009) Sepsis-induced myopathy. Crit Care Med 37:S354-67 |
| Supinski, Gerald S; Ji, Xinying; Callahan, Leigh Ann (2009) The JNK MAP kinase pathway contributes to the development of endotoxin-induced diaphragm caspase activation. Am J Physiol Regul Integr Comp Physiol 297:R825-34 |
| Callahan, Leigh Ann; Supinski, Gerald S (2005) Downregulation of diaphragm electron transport chain and glycolytic enzyme gene expression in sepsis. J Appl Physiol 99:1120-6 |
| Supinski, Gerald S; Callahan, Leigh A (2005) Diaphragmatic free radical generation increases in an animal model of heart failure. J Appl Physiol 99:1078-84 |
