Nrf2 pathway potentially confers protection against cigarette smoke-induced sarcopenia in a mouse model

Background Nuclear factor erythroid-2-related factor 2 ( Nrf2 ) could alleviate chronic obstructive pulmonary disease (COPD)-induced muscle dysfunction, and this study aimed to explore the specific mechanisms involved. Methods We successfully established a 12-week cigarette smoke-induced mouse model to replicate COPD-related sarcopenia. The Nrf2 agonist sulforaphane (SFN) and inhibitor ML385 were used to comprehensively assess the regulatory function of Nrf2 in COPD-related sarcopenia. Lung function tests, muscle tension measurements, flow cytometry, H&E staining, qRT-PCR, Western blotting, and biochemical assays were performed to evaluate changes in inflammation, oxidative stress, autophagy, and the Nrf2 /Keap1 axis, so as to verify the pivotal role of Nrf2 signaling in modulating immune responses and skeletal muscle injury from multiple perspectives. Results In the COPD model group, FEV 0.1 /FVC was significantly decreased ( p  < 0.05), along with markedly reduced quadriceps muscle mass and grip strength ( p  < 0.05). Additionally, the numbers of neutrophils, monocytes, and macrophages in the lung tissues were notably increased ( p  < 0.05), accompanied by elevated levels of inflammatory cytokines IL-1b, IL-6, and IL-18 ( p  < 0.05). The level of Malondialdehyde (MDA) was increased ( p  < 0.05), while that of heme oxygenase 1 (HO-1), glutathione-S-transferase (GST), and total superoxide dismutase (T-SOD) was decreased ( p  < 0.05). SFN treatment significantly upregulated Nrf2 and downregulated Keap1 expression ( p  < 0.05), reversed the changes in inflammatory and oxidative stress markers ( p  < 0.05), and inhibited the protein levels of ATG7 and LC3 ( p  < 0.05). In contrast, the ML385-treated group showed opposite trends. Conclusion The present study demonstrated that the Nrf2 pathway played a key role in the regulation of inflammatory response, oxidative stress and autophagy in COPD-associated sarcopenia.