Nuclear Factor Erythroid 2-Related Factor 2 and Its Targets in Skeletal Muscle Repair and Regeneration

<b><i>Significance:</i></b> Skeletal muscles have a robust regenerative capacity in response to acute and chronic injuries. Muscle repair and redox homeostasis are intimately linked; increased generation of reactive oxygen species leads to cellular dysfunction and contributes to muscle wasting and progression of muscle diseases. In exemplary muscle disease, Duchenne muscular dystrophy (DMD), caused by mutations in the <i>DMD</i> gene that encodes the muscle structural protein dystrophin, the regeneration machinery is severely compromised, while oxidative stress contributes to the progression of the disease. The nuclear factor erythroid 2-related factor 2 (NRF2) and its target genes, including heme oxygenase-1 (HO-1), provide protective mechanisms against oxidative insults. <b><i>Recent Advances:</i></b> Relevant advances have been evolving in recent years in understanding the mechanisms by which NRF2 regulates processes that contribute to effective muscle regeneration. To this end, pathways related to muscle satellite cell differentiation, oxidative stress, mitochondrial metabolism, inflammation, fibrosis, and angiogenesis have been studied. The regulatory role of NRF2 in skeletal muscle ferroptosis has been also suggested. Animal studies have shown that NRF2 pathway activation can stop or reverse skeletal muscle pathology, especially when endogenous stress defence mechanisms are imbalanced. <b><i>Critical Issues:</i></b> Despite the growing recognition of NRF2 as a factor that regulates various aspects of muscle regeneration, the mechanistic impact on muscle pathology in various models of muscle injury remains imprecise. <b><i>Future Directions:</i></b> Further studies are necessary to fully uncover the role of NRF2 in muscle regeneration, both in physiological and pathological conditions, and to investigate the possibilities for development of new therapeutic modalities. <i>Antioxid. Redox Signal.</i> 38, 619-642.