Abstract
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, FEV0.1/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.