Role of Nrf2 and exercise in alleviating COPD-induced skeletal muscle dysfunction

Chronic obstructive pulmonary disease (COPD) is a complex chronic respiratory disease with cumulative impacts on multiple systems, exhibiting significant extrapulmonary impacts, and posing a serious public health problem. Skeletal muscle dysfunction is one of the most pronounced extrapulmonary effects in patients with COPD, which severely affects patient prognosis and mortality primarily through reduced productivity resulting from muscle structural and functional alterations. Although the detailed pathogenesis of COPD has not been fully determined, some researchers agree that oxidative stress plays a significant role. Oxidative stress not only catalyzes the progression of pulmonary symptoms but also drives the development of skeletal muscle dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2), is a key transcription factor that regulates the antioxidant response and plays an enormous role in combating oxidative stress. In this review, we have summarized current research on oxidative stress damage to COPD skeletal muscle and analyzed the role of Nrf2 in improving skeletal muscle dysfunction in COPD through exercise. The results suggest that oxidative stress drives the occurrence and development of skeletal muscle dysfunction in COPD. Exercise may improve skeletal muscle dysfunction in patients with COPD by promoting the dissociation of Kelch-like ECH-associated protein 1 (Keap1) and Nrf2, inducing sequestosome1(p62) phosphorylation to bind with Keap1 competitively leading to Nrf2 stabilization and improving dynamin-related protein 1-dependent mitochondrial fission. Nrf2 may be a key target for exercise anti-oxidative stress to alleviate skeletal muscle dysfunction in COPD. Graphical abstract