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Cardiovascular Research 2005 65(2):411-418; doi:10.1016/j.cardiores.2004.10.025
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Copyright © 2004, European Society of Cardiology

Regional absence of mitochondria causing energy depletion in the myocardium of muscle LIM protein knockout mice

Bianca J.C. van den Boscha, Caroline M.M. van den Burga, Kees Schoonderwoerdb,c, Patrick J. Lindseya, Hans R. Scholtec, René F.M. de Cood, Eva van Rooija,e, Howard A. Rockmanf, Pieter A. Doevendanse,g and Hubert J.M. Smeetsa,*

aCardiovascular Research Institute Maastricht (CARIM), Department of Genetics and Cell Biology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
bDepartment of Clinical Genetics, Erasmus MC Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
cDepartment of Biochemistry, Erasmus MC Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
dDepartment of Child Neurology, Erasmus MC Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
eDepartment of Cardiology of the Heart Lung Centre Utrecht (UMCU), P.O. Box 85500, 3508 GA Utrecht, The Netherlands
fDepartment of Medicine, Duke University Medical Center, DUMC 3104, 226 CARL Building, Research Drive, Durham, NC 27710, USA
gInteruniversity Cardiology Institute of the Netherlands (ICIN), P.O. Box 19258, 3501 DG Utrecht, The Netherlands

* Corresponding author. Tel.: +31 43 3875843/3875803; fax: +31 43 3877877. Email address: Bert.Smeets{at}molcelb.unimaas.nl

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 1{alpha} (PGC-1{alpha}), 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.

KEYWORDS Cardiomyopathy; Heart failure; Cytoskeleton; Mitochondria; Oxidative phosphorylation

Time for primary review 19 days


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