Frontiers in Physiology (Feb 2014)

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

  • Ponvijay eKombairaju,
  • Jaclyn P Kerr,
  • Joseph A Roche,
  • Stephen J.P Pratt,
  • Richard M Lovering,
  • Thomas E Sussan,
  • Jung-Hyun eKim,
  • Guoli eShi,
  • Shyam eBiswal,
  • Christopher William Ward

DOI
https://doi.org/10.3389/fphys.2014.00057
Journal volume & issue
Vol. 5

Abstract

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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 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.

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