Abstract:
OBJECTIVE:Defects in myocardial mitochondrial structure and function have been associated with heart failure in humans and animal models. Mice lacking the muscle LIM protein (MLP) develop morphological and clinical signs resembling human dilated cardiomyopathy and heart failure. We tested the hypothesis that defects in the cytoskeleton lead to dilated cardiomyopathy through mitochondrial dysfunction in the MLP mouse model. METHODS AND RESULTS:Oxidative phosphorylation activity was determined in left ventricles of MLP knockout (KO) mice and control littermates by measuring complex activities of the electron transport chain (I-IV) and ATP synthase (complex V). All complexes and citrate synthase (CS) showed decreased activities in the KO mice, although activity per amount of CS, a measure for mitochondrial density, was normal. Light and electron microscopy revealed a disorganization of mitochondria and a dramatic decrease in mitochondrial density, even revealing regions completely lacking mitochondria in the KO hearts. Real-time PCR analysis showed decreased transcript levels of mtDNA and nuclear encoded mitochondrial genes and of peroxisome proliferator activated receptor gamma co-activator 1alpha (PGC-1alpha), a key regulator of mitochondrial biogenesis. MtDNA copy number (ratio mtDNA/nuclear DNA) was slightly increased in the MLP KO mice. CONCLUSION:Our results show that the absence of MLP causes a local loss of mitochondria. We hypothesize that this is caused by a disturbed interaction between cytoskeleton and mitochondria, which interferes with energy sensing and energy transfer. Recovery of energy depletion by stimulating mitochondrial biogenesis might be a useful therapeutic strategy for improving the energy imbalance in heart failure.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
van den Bosch BJ,van den Burg CM,Schoonderwoerd K,Lindsey PJ,Scholte HR,de Coo RF,van Rooij E,Rockman HA,Doevendans PA,Smeets HJdoi
10.1016/j.cardiores.2004.10.025subject
Has Abstractpub_date
2005-02-01 00:00:00pages
411-8issue
2eissn
0008-6363issn
1755-3245pii
S0008-6363(04)00479-1journal_volume
65pub_type
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