Excessive linoleic acid induces muscle oxidative stress through 5-lipoxygenase-dependent peroxidation

• Published in: Redox biology 2024-05, Vol.71, p.103096, Article 103096
• Main Authors: Cao, Xiufei, Guo, Huixing, Dai, Yongjun, Jiang, Guangzhen, Liu, Wenbin, Li, Xiangfei, Zhang, Dingdong, Huang, Yangyang, Wang, Xi, Hua, Haokun, Wang, Jianfeng, Chen, Keke, Chi, Cheng, Liu, Hengtong
• Format: Article
• Language: English
• Subjects: 5-Lipoxygenase; cAMP/PKA signaling pathway; Crab muscle; Linoleic acid; Oxidative stress; Research Paper; Volatile aldehydes
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2024.103096

Oxidative stress in muscles is closely related to the occurrence of insulin resistance, muscle weakness and atrophy, age-related sarcopenia, and cancer. Aldehydes, a primary oxidation intermediate of polyunsaturated fatty acids, have been proven to be an important trigger for oxidative stress. However, the potential role of linoleic acid (LA) as a donor for volatile aldehydes to trigger oxidative stress has not been reported. Here, we reported that excessive dietary LA caused muscle redox imbalance and volatile aldehydes containing hexanal, 2-hexenal, and nonanal were the main metabolites leading to oxidative stress. Importantly, we identified 5-lipoxygenase (5-LOX) as a key enzyme mediating LA peroxidation in crustaceans for the first time. The inhibition of 5-LOX significantly suppressed the content of aldehydes produced by excessive LA. Mechanistically, the activation of the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway facilitated the translocation of 5-LOX from the nucleus to the cytoplasm, where 5-LOX oxidized LA, leading to oxidative stress through the generation of aldehydes. This study suggests that 5-LOX is a potential target to prevent the production of harmful aldehydes. [Display omitted] •Excessive LA triggers oxidative stress in muscle cells by producing volatile aldehydes.•LA-mediated production of volatile aldehydes, such as hexanal, hexenal, and nonanal, is 5-LOX-dependent.•The cAMP-PKA pathway promotes LA peroxidation by increasing 5-LOX in the cytoplasm.