Abnormal cardiac and skeletal muscle mitochondrial function in pacing-induced cardiac failure.
BACKGROUND
Previous studies have shown that marked changes in myocardial mitochondrial structure and function occur in human cardiac failure. To further understand the cellular events and to clarify their role in the pathology of cardiac failure, we have examined mitochondrial enzymatic function and peptide content, and mitochondrial DNA (mtDNA) integrity in a canine model of pacing-induced cardiac failure.


METHODS
Myocardium and skeletal muscle 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 cardiac tumor necrosis factor-alpha (TNF-alpha), and of total aldehyde content in left ventricle were also assessed.


RESULTS
Specific activity levels of complex III and V were significantly lower in both myocardial and skeletal muscle 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 mtDNA deletions were found to be more likely present in myocardial tissue of paced as compared to control animals, albeit at a relatively low proportion of mtDNA molecules (<0.01% of wild-type). In addition, the reduction in complex III and V activities was correlated with elevated plasma and cardiac TNF-alpha levels. Significant increases in left ventricle aldehyde levels were also found.


CONCLUSIONS
Our data show reductions in specific mitochondrial respiratory enzyme activities in pacing-induced heart failure which is not likely due to overall decreases in mitochondrial number, or necrosis. Our findings suggest a role for mitochondrial dysfunction in the pathogenesis of cardiac failure and may indicate a commonality in the signaling for pacing-induced mitochondrial dysfunction in myocardial and skeletal muscle. Increased levels of TNF-alpha and oxidative stress appear to play a contributory role.
Marín-García
J
J
The Molecular Cardiology and Neuromuscular Institute, 75 Raritan Ave., Highland Park, NJ 08904, USA. tmci@att.net
Goldenthal
M J
MJ
Moe
G W
GW
D000251:Adenosine Triphosphatases / Q000032:analysis; D000447:Aldehydes / Q000032:analysis; D000818:Animals; D002304:Cardiac Pacing, Artificial; D002352:Carrier Proteins; D016022:Case-Control Studies; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004285:Dogs; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III / Q000032:analysis; D017353:Gene Deletion; D006333:Heart Failure / Q000378:metabolism*; D006352:Heart Ventricles / Q000737:chemistry; D015151:Immunoblotting / Q000379:methods; D008565:Membrane Proteins / Q000032:analysis; D008928:Mitochondria / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases; D023421:Models, Animal; D009097:Multienzyme Complexes / Q000032:analysis*; D010088:Oxidoreductases / Q000032:analysis; D016133:Polymerase Chain Reaction / Q000379:methods; D013385:Succinate Dehydrogenase / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000447:Aldehydes; D002352:Carrier Proteins; D004272:DNA, Mitochondrial; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D014409:Tumor Necrosis Factor-alpha; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D002950:Citrate (si)-Synthase; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; D014450:Electron Transport Complex III; C020439:oligomycin sensitivity-conferring protein