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Reciprocal amplification of ROS and Ca(2+) signals in stressed mdx dystrophic skeletal muscle fibers.
- Source :
-
Pflugers Archiv : European journal of physiology [Pflugers Arch] 2009 Sep; Vol. 458 (5), pp. 915-28. Date of Electronic Publication: 2009 Apr 22. - Publication Year :
- 2009
-
Abstract
- Muscular dystrophies are among the most severe inherited muscle diseases. The genetic defect is a mutation in the gene for dystrophin, a cytoskeletal protein which protects muscle cells from mechanical damage. Mechanical stress, applied as osmotic shock, elicits an abnormal surge of Ca(2+) spark-like events in skeletal muscle fibers from dystrophin deficient (mdx) mice. Previous studies suggested a link between changes in the intracellular redox environment and appearance of Ca(2+) sparks in normal mammalian skeletal muscle. Here, we tested whether the exaggerated Ca(2+) responses in mdx fibers are related to oxidative stress. Localized intracellular and mitochondrial Ca(2+) transients, as well as ROS production, were assessed with confocal microscopy. The rate of basal cellular but not mitochondrial ROS generation was significantly higher in mdx cells. This difference was abolished by pre-incubation of mdx fibers with an inhibitor of NAD(P)H oxidase. In addition, immunoblotting showed a significantly stronger expression of NAD(P)H oxidase in mdx muscle, suggesting a major contribution of this enzyme to oxidative stress in mdx fibers. Osmotic shock produced an abnormal and persistent Ca(2+) spark activity, which was suppressed by ROS-reducing agents and by inhibitors of NAD(P)H oxidase. These Ca(2+) signals resulted in mitochondrial Ca(2+) accumulation in mdx fibers and an additional boost in cellular and mitochondrial ROS production. Taken together, our results indicate that the excessive ROS production and the simultaneous activation of abnormal Ca(2+) signals amplify each other, finally culminating in a vicious cycle of damaging events, which may contribute to the abnormal stress sensitivity in dystrophic skeletal muscle.
- Subjects :
- Animals
Calcium Signaling drug effects
Enzyme Inhibitors pharmacology
Free Radical Scavengers pharmacology
Free Radicals metabolism
Male
Membrane Glycoproteins antagonists & inhibitors
Membrane Glycoproteins metabolism
Membrane Potential, Mitochondrial physiology
Mice
Mice, Inbred C57BL
Mice, Inbred mdx
Mitochondria metabolism
Muscular Dystrophy, Duchenne physiopathology
NADPH Oxidase 2
NADPH Oxidases antagonists & inhibitors
NADPH Oxidases metabolism
Osmotic Pressure physiology
Reactive Nitrogen Species metabolism
Calcium Signaling physiology
Muscle Fibers, Skeletal metabolism
Muscular Dystrophy, Duchenne metabolism
Oxidative Stress physiology
Reactive Oxygen Species metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1432-2013
- Volume :
- 458
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Pflugers Archiv : European journal of physiology
- Publication Type :
- Academic Journal
- Accession number :
- 19387681
- Full Text :
- https://doi.org/10.1007/s00424-009-0670-2