Nrf2 deficiency induces skeletal muscle mitochondrial dysfunction: a proteomics/bioinformatics approach, 2020, Willis and Deane

Andy · Oct 7, 2020

In mice.

Intracellular redox homeostasis is crucial for maintaining healthy skeletal muscle. Substantial redox imbalance due to excess reactive oxygen species (ROS) production is consequently associated with muscle fatigue, functional decline, metabolic dysfunction and even muscle wasting. The nuclear factor erythroid-derived 2 (Nrf2)/Kelch ECH-associated protein 1 (Keap1) complex is a redox-sensitive transcriptional regulatory system pivotal for the regulation of redox homeostasis, where the cytoplasmic repressor protein, Keap1, senses intracellular ROS and electrophiles, and the transcription factor, Nrf2, promotes antioxidant and other cytoprotective (e.g. anti-inflammation, metabolism) gene expression.

In the resting state, Nrf2 is sequestered in the cytoplasm by Keap1 and targeted for proteasomal degradation and thus antioxidant expression remains low. However, in response to cellular stress, intracellular ROS levels increase and several Keap1 cystine residues become oxidised, facilitating the liberation of Nrf2 from Keap1. Nrf2 therein translocates to the nucleus where it binds to antioxidant response elements, in turn promoting the transcription of antioxidant enzyme genes. Targeted analytical research has shown that exercise stress induces Nrf2-mediated antioxidant expression in mouse skeletal muscle (Li et al., 2015) and, conversely, that Nrf2 deficient mice display higher intramyocellular ROS levels and attenuated antioxidant enzyme abundance (Miller et al., 2012).

Consequently, impaired Nrf2/Keap1 function has been implicated in skeletal myopathy and disease and the Nrf2/Keap1 complex has been suggested as a promising therapeutic target against such pathologies. However, despite growing evidence for the Nrf2/Keap1 complex as a powerful intramuscular antioxidant system, the precise biological implications of Nrf2 in skeletal muscle tissue remain poorly defined.
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Open access PDF available at https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP280758

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Nrf2 deficiency induces skeletal muscle mitochondrial dysfunction: a proteomics/bioinformatics approach, 2020, Willis and Deane

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Nrf2 deficiency induces skeletal muscle mitochondrial dysfunction: a proteomics/bioinformatics approach, 2020, Willis and Deane

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