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Reciprocal amplification of ROS and Ca(2+) signals in stressed mdx dystrophic skeletal muscle fibers.

Authors :
Shkryl VM
Martins AS
Ullrich ND
Nowycky MC
Niggli E
Shirokova N
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.

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