Reciprocal amplification of ROS and Ca2+ signals in stressed mdx dystrophic skeletal muscle fibers

Vyacheslav M. Shkryl, Adriano S. Martins, Nina D. Ullrich, Martha C. Nowycky, Ernst Niggli, Natalia Shirokova

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

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 Ca2+ 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 Ca2+ sparks in normal mammalian skeletal muscle. Here, we tested whether the exaggerated Ca2+ responses in mdx fibers are related to oxidative stress. Localized intracellular and mitochondrial Ca2+ 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 Ca2+ spark activity, which was suppressed by ROS-reducing agents and by inhibitors of NAD(P)H oxidase. These Ca2+ signals resulted in mitochondrial Ca2+ 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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)915-928
Number of pages14
JournalPflugers Archiv European Journal of Physiology
Volume458
Issue number5
DOIs
StatePublished - Sep 2009

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

Keywords

  • Ca2+ sparks
  • Confocal microscopy
  • Mdx mice
  • ROS
  • Skeletal muscle

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