Abnormal cardiac and skeletal muscle mitochondrial function in pacing-induced cardiac failure

Background: Previous studies have shown that marked changes in myocardial m itochondrial structure and function occur in human cardiac failure. To furt her understand the cellular events and to clarify their role in the patholo gy of cardiac failure, we have examined mitochondrial enzymatic function an d peptide content, and mitochondrial DNA (mtDNA) integrity in a canine mode l of pacing-induced cardiac failure. Methods: Myocardium and skeletal muscl e tissues were evaluated for levels of respiratory complex I-V and citrate synthase activities, large-scale mtDNA deletions as well as peptide content of specific mitochondrial enzyme subunits. Levels of circulating and cardi ac tumor necrosis factor-alpha (TNF-alpha), and of total aldehyde content i n left ventricle were also assessed. Results: Specific activity levels of c omplex III and V were significantly lower in both myocardial and skeletal m uscle tissues of paced animals compared to controls. In contrast, activity levels of complex I, II, IV and citrate synthase were unchanged, as was the peptide content of specific mitochondrial enzyme subunits. Large-scale mtD NA deletions were found to be more likely present in myocardial tissue of p aced as compared to control animals, albeit at a relatively low proportion of mtDNA molecules (<0.01% of wild-type). In addition, the reduction in com plex III and V activities was correlated with elevated plasma and cardiac T NF-alpha levels. Significant increases in left ventricle aldehyde levels we re also found. Conclusions: Our data show reductions in specific mitochondr ial respiratory enzyme activities in pacing-induced heart failure which is not likely due to overall decreases in mitochondrial number, or necrosis. O ur findings suggest a role for mitochondrial dysfunction in the pathogenesi s of cardiac failure and may indicate a commonality in the signaling for pa cing-induced mitochondrial dysfunction in myocardial and skeletal muscle. I ncreased levels of TNF-alpha and oxidative stress appear to play a contribu tory role. (C) 2001 Elsevier Science B.V. All rights reserved.