FREE RADICALS AND MUSCLE DYSFUNCTION IN HEART FAILURE
Principal Investigator: GERALD SUPINSKI
Affiliation: University of Kentucky
Abstract: 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.
Funding Period: 2000-08-01 - 2007-02-28
more information: NIH RePORT
- Diaphragmatic free radical generation increases in an animal model of heart failureGerald S Supinski
Pulmonary and Critical Care Division, Department of Medicine, Medical College of Georgia, Augusta, GA 30912 3135, USA
J Appl Physiol (1985) 99:1078-84. 2005..03). These findings indicate that cardiac dysfunction due to coronary ligation increases diaphragm free radical generation and that free radicals evoke reductions in diaphragm force generation...
- Downregulation of diaphragm electron transport chain and glycolytic enzyme gene expression in sepsisLeigh Ann Callahan
Div of Pulmonary and Critical Care Medicine, 1120 15th St, Rm BBR 5513, Medical College of Georgia, Augusta, GA 30912 3135, USA
J Appl Physiol (1985) 99:1120-6. 2005....
- Calpain activation contributes to endotoxin-induced diaphragmatic dysfunctionGerald S Supinski
Department of Medicine, 740 South Limestone, University of Kentucky, Lexington, KY 40536 0284, USA
Am J Respir Cell Mol Biol 42:80-7. 2010..Moreover, calpain inhibition attenuates endotoxin-induced diaphragm weakness, suggesting that such inhibitors may be a potential treatment to improve respiratory muscle function in infected patients...
- Effect of proteasome inhibitors on endotoxin-induced diaphragm dysfunctionG S Supinski
Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky, Lexington, KY 40536 0284, USA
Am J Physiol Lung Cell Mol Physiol 296:L994-L1001. 2009..01); caspase-3 activity remained high when either MG132, epoxomicin, or bortezomib were given. These data suggest proteasomal inhibitors are not an adequate treatment to prevent endotoxin-induced diaphragmatic dysfunction...
- The JNK MAP kinase pathway contributes to the development of endotoxin-induced diaphragm caspase activationGerald S Supinski
Division of Pulmonary, Critical Care and Sleep Medicine, University of Kentucky, Lexington, Kentucky, USA
Am J Physiol Regul Integr Comp Physiol 297:R825-34. 2009..JNK inhibition also prevented caspase 8 activation in cytokine-treated muscle cells (P < 0.001). These data implicate JNK activation as a major factor mediating inflammation-induced skeletal muscle caspase 8 activation and weakness...
- MitoQ administration prevents endotoxin-induced cardiac dysfunctionG S Supinski
Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky, Lexington, Kentucky 40536 0284, USA
Am J Physiol Regul Integr Comp Physiol 297:R1095-102. 2009..01). These data demonstrate that MitoQ is a potent inhibitor of endotoxin-induced mitochondrial and cardiac abnormalities. We speculate that this agent may prove a novel therapy for sepsis-induced cardiac dysfunction...
- Sepsis-induced myopathyLeigh Ann Callahan
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Kentucky, Lexington, KY, USA
Crit Care Med 37:S354-67. 2009..Emerging data suggest that targeted inhibition of these pathways may alter the evolution and progression of sepsis-induced myopathy and potentially reduce the occurrence of sepsis-mediated acquired weakness syndromes...