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.

Nrf2 augments skeletal muscle regeneration after ischaemia–reperfusion injury

“…Sustained high ROS levels or, accordingly, a depletion of antioxidant defence, such as glutathione, led to decreased MyoD expression and subsequently to impaired myogenesis in vitro [22,23]. Comparable effects were recently observed in skeletal muscles in vivo, where an impaired antioxidant stress defence, including Nrf2 and glutathione, led to higher ROS levels, functional deficits and histopathological alterations [24,25].…”

Mitochondria in the middle: exercise preconditioning protection of striated muscle

“…dysferlin) are mutated (Kombairaju et al . ). Nox2 also appears hyper‐sensitive and up‐regulated in skeletal muscle during mechanical unloading (Lawler et al .…”

Butyrate prevents muscle atrophy after sciatic nerve crush

“…34,40,41 Nrf2 protects against muscle atrophy due to denervation, aging, and inflammation and is a potential target for skeletal muscle disease. [42][43][44] While butyrate had no effect on mitochondrial ROS production induced by nerve injury, it did increase MnSOD and catalase activity, resulting in reduced oxidative damage. How HDACs regulate antioxidant enzymes is not known; a recent study found that a class I-specific HDAC inhibitor induces MnSOD and catalase after cardiac ischemia, 41 suggesting butyrate modulates oxidative stress by inhibiting class I HDAC.…”

“…Of interest, several studies have shown that HDAC inhibition activates the nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) antioxidant response pathway . Nrf2 protects against muscle atrophy due to denervation, aging, and inflammation and is a potential target for skeletal muscle disease . While butyrate had no effect on mitochondrial ROS production induced by nerve injury, it did increase MnSOD and catalase activity, resulting in reduced oxidative damage.…”