Genetic silencing of Nrf2 enhances X-ROS in dysferlin-deficient muscle

Ponvijay Kombairaju, Jaclyn P. Kerr, Joseph A. Roche, Stephen J.P. Pratt, Richard M. Lovering, Thomas E. Sussan, Jung Hyun Kim, Guoli Shi, Shyam Biswal, Christopher W. Ward

Research output: Contribution to journalArticlepeer-review

Abstract

Oxidative stress is a critical disease modifier in the muscular dystrophies. Recently, we discovered a pathway by which mechanical stretch activates NADPH Oxidase 2 (Nox2) dependent ROS generation (X-ROS). Our work in dystrophic skeletal muscle revealed that X-ROS is excessive in dystrophin-deficient (mdx) skeletal muscle and contributes to muscle injury susceptibility, a hallmark of the dystrophic process. We also observed widespread alterations in the expression of genes associated with the X-ROS pathway and redox homeostasis in muscles from both Duchenne muscular dystrophy patients and mdx mice. As nuclear factor erythroid 2-related factor 2 (Nrf2) plays an essential role in the transcriptional regulation of genes involved in redox homeostasis, we hypothesized that Nrf2 deficiency may contribute to enhanced X-ROS signaling by reducing redox buffering. To directly test the effect of diminished Nrf2 activity, Nrf2 was genetically silenced in the A/J model of dysferlinopathy-a model with a mild histopathologic and functional phenotype. Nrf2-deficient A/J mice exhibited significant muscle-specific functional deficits, histopathologic abnormalities, and dramatically enhanced X-ROS compared to control A/J and WT mice, both with functional Nrf2. Having identified that reduced Nrf2 activity is a negative disease modifier, we propose that strategies targeting Nrf2 activation may address the generalized reduction in redox homeostasis to halt or slow dystrophic progression.

Original languageEnglish (US)
Article numberArticle 57
JournalFrontiers in Physiology
Volume5 FEB
DOIs
StatePublished - 2014

Keywords

  • Dysferlin
  • Dystrophy
  • Nrf2
  • ROS
  • X-ROS

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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