title: Genetic silencing of Nrf2 enhances X-ROS in dysferlin-deficient muscle.
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.
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University Baltimore, MD, USA.
authors.forename: Ponvijay
authors.initials: P
authors.lastname: Kombairaju
authors.affiliation: Department of Physiology, University of Maryland School of Medicine Baltimore, MD, USA.
authors.forename: Jaclyn P
authors.initials: JP
authors.lastname: Kerr
authors.affiliation: Department of Physiology, University of Maryland School of Medicine Baltimore, MD, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Roche
authors.affiliation: Department of Orthopaedics, University of Maryland School of Medicine Baltimore, MD, USA.
authors.forename: Stephen J P
authors.initials: SJP
authors.lastname: Pratt
authors.affiliation: Department of Orthopaedics, University of Maryland School of Medicine Baltimore, MD, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Lovering
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University Baltimore, MD, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Sussan
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University Baltimore, MD, USA.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Organizational Systems and Adult Health, University of Maryland School of Nursing Baltimore, MD, USA.
authors.forename: Guoli
authors.initials: G
authors.lastname: Shi
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University Baltimore, MD, USA.
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
authors.affiliation: Department of Organizational Systems and Adult Health, University of Maryland School of Nursing Baltimore, MD, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ward
keywords: Nrf2; ROS; X-ROS; dysferlin; dystrophy