Cardiovascular Research Advance Access originally published online on December 4, 2007
Cardiovascular Research 2008 77(4):766-773; doi:10.1093/cvr/cvm089
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Dystrophic cardiomyopathy: amplification of cellular damage by Ca2+ signalling and reactive oxygen species-generating pathways
1 Department of Physiology, University of Bern, Bern, Switzerland
2 Department of Pharmacology and Physiology, UMDNJ—New Jersey Medical School, 185 S. Orange Avenue, Newark, NJ 07103, USA
* Corresponding author. Tel: +1 973 972 8877; fax: +1 973 972 7950. E-mail address: nshiroko{at}umdnj.edu
Aims: Cardiac myopathies are the second leading cause of death in patients with Duchenne and Becker muscular dystrophy, the two most common and severe forms of a disabling striated muscle disease. Although the genetic defect has been identified as mutations of the dystrophin gene, very little is known about the molecular and cellular events leading to progressive cardiac muscle damage. Dystrophin is a protein linking the cytoskeleton to a complex of transmembrane proteins that interact with the extracellular matrix. The fragility of the cell membrane resulting from the lack of dystrophin is thought to cause an excessive susceptibility to mechanical stress. Here, we examined cellular mechanisms linking the initial membrane damage to the dysfunction of dystrophic heart.
Methods and results: Cardiac ventricular myocytes were enzymatically isolated from 5- to 9-month-old dystrophic mdx and wild-type (WT) mice. Cells were exposed to mechanical stress, applied as osmotic shock. Stress-induced cytosolic and mitochondrial Ca2+ signals, production of reactive oxygen species (ROS), and mitochondrial membrane potential were monitored with confocal microscopy and fluorescent indicators. Pharmacological tools were used to scavenge ROS and to identify their possible sources. Osmotic shock triggered excessive cytosolic Ca2+ signals, often lasting for several minutes, in 82% of mdx cells. In contrast, only 47% of the WT cardiomyocytes responded with transient and moderate intracellular Ca2+ signals. On average, the reaction was 6-fold larger in mdx cells. Removal of extracellular Ca2+ abolished these responses, implicating Ca2+ influx as a trigger for abnormal Ca2+ signalling. Our further experiments revealed that osmotic stress in mdx cells produced an increase in ROS production and mitochondrial Ca2+ overload. The latter was followed by collapse of the mitochondrial membrane potential, an early sign of cell death.
Conclusion: Overall, our findings reveal that excessive intracellular Ca2+ signals and ROS generation link the initial sarcolemmal injury to mitochondrial dysfunctions. The latter possibly contribute to the loss of functional cardiac myocytes and heart failure in dystrophy. Understanding the sequence of events of dystrophic cell damage and the deleterious amplification systems involved, including several positive feed-back loops, may allow for a rational development of novel therapeutic strategies.
KEYWORDS Calcium (cellular); Mitochondria; Myocytes; Oxygen radicals; SR (function)
Time for primary review: 34 days
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