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.