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Modifications of proteins by 4-hydroxy-2-nonenal in the ventilatory muscles of rats

¹Critical Care and Respiratory Divisions, Royal Victoria Hospital, McGill University Health Centre, and Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada; ²Muscle and Respiratory System Research Unit, Institut Municipal d'Investigació Mèdica, Departament de Ciències Experimental de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain; and ³Department of Critical Care and Pulmonary Services, University of Athens Medical School, Evangelismos Hospital, Athens, Greece

Submitted 2 August 2005 ; accepted in final form 13 December 2005

Although 4-hydroxy-2-nonenal (HNE, a product of lipid peroxidation) is a major cause of oxidative damage inside skeletal muscles, the exact proteins modified by HNE are unknown. We used two-dimensional electrophoresis, immunoblotting, and mass spectrometry to identify selective proteins targeted by HNE inside the diaphragm of rats under two conditions: severe sepsis [induced by E. coli lipopolysaccharides (LPS)] and during strenuous muscle contractions elicited by severe inspiratory resistive loading (IRL). Diaphragm HNE-protein adduct formation (detected with a polyclonal antibody) increased significantly after 1 and 3 h of LPS injection with a return to baseline values thereafter. Similarly, HNE-protein adduct formation inside the diaphragm rose significantly after 6 but not 3 h of IRL. Mass spectrometry analysis of HNE-modified proteins revealed enolase 3b, aldolase and triosephosphate isomerase 1, creatine kinase, carbonic anyhdrase III, aconitase 2, dihydrolipoamide dehydrogenase, and electron transfer flavoprotein-. Measurements of in vitro enolase activity in the presence of pure HNE revealed that HNE significantly attenuated enolase activity in a dose-dependent fashion, suggesting that HNE-derived modifications have inhibitory effects on enzyme activity. We conclude that lipid peroxidation products may inhibit muscle contractile performance through selective targeting of enzymes involved in glycolysis, energy production as well as CO₂ hydration.

oxygen radicals; protein oxidation; carbonyl formation; sepsis; skeletal muscle; enolase

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				T. Vassilakopoulos and S. N. A. Hussain Ventilatory muscle activation and inflammation: cytokines, reactive oxygen species, and nitric oxide J Appl Physiol, April 1, 2007; 102(4): 1687 - 1695. [Abstract] [Full Text] [PDF]