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

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月25日

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  • Pin Guan,
  • Wentao Cai,
  • Chunrong Zhong,
  • Chunmei Wu

摘要

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.