title: Regional absence of mitochondria causing energy depletion in the myocardium of muscle LIM protein knockout mice.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiovascular Research Institute Maastricht (CARIM), Department of Genetics and Cell Biology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: Bianca J C
authors.initials: BJ
authors.lastname: van den Bosch
authors.forename: Caroline M M
authors.initials: CM
authors.lastname: van den Burg
authors.forename: Kees
authors.initials: K
authors.lastname: Schoonderwoerd
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Lindsey
authors.forename: Hans R
authors.initials: HR
authors.lastname: Scholte
authors.forename: René F M
authors.initials: RF
authors.lastname: de Coo
authors.forename: Eva
authors.initials: E
authors.lastname: van Rooij
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Hubert J M
authors.initials: HJ
authors.lastname: Smeets
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000378:metabolism / Q000648:ultrastructure*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D010085:Oxidative Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D060588:LIM Domain Proteins; D009124:Muscle Proteins; C090114:cysteine and glycine-rich protein 3