Graduate School of Science, Nagoya City University, Nagoya, Japan.
Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
J Physiol. 2024 Sep;602(17):4215-4235. doi: 10.1113/JP286460. Epub 2024 Aug 21.
Oxidative stress contributes to the loss of skeletal muscle mass and function in cancer cachexia. However, this outcome may be mitigated by an improved endogenous antioxidant defence system. Here, using the well-established oxidative stress-inducing muscle atrophy model of Lewis lung carcinoma (LLC) in 13-week-old male C57BL/6J mice, we demonstrate that extracellular superoxide dismutase (EcSOD) levels increase in the cachexia-prone extensor digitorum longus muscle. LLC transplantation significantly increased interleukin-1β (IL-1β) expression and release from extensor digitorum longus muscle fibres. Moreover, IL-1β treatment of C2C12 myotubes increased NBR1, p62 phosphorylation at Ser351, Nrf2 nuclear translocation and EcSOD protein expression. Additional studies in vivo indicated that intramuscular IL-1β injection is sufficient to stimulate EcSOD expression, which is prevented by muscle-specific knockout of p62 and Nrf2 (i.e. in p62 skmKO and Nrf2 skmKO mice, respectively). Finally, since an increase in circulating IL-1β may lead to unwanted outcomes, we demonstrate that targeting this pathway at p62 is sufficient to drive muscle EcSOD expression in an Nrf2-dependent manner. In summary, cancer cachexia increases EcSOD expression in extensor digitorum longus muscle via muscle-derived IL-1β-induced upregulation of p62 phosphorylation and Nrf2 activation. These findings provide further mechanistic evidence for the therapeutic potential of p62 and Nrf2 to mitigate cancer cachexia-induced muscle atrophy. KEY POINTS: Oxidative stress plays an important role in muscle atrophy during cancer cachexia. EcSOD, which mitigates muscle loss during oxidative stress, is upregulated in 13-week-old male C57BL/6J mice of extensor digitorum longus muscles during cancer cachexia. Using mouse and cellular models, we demonstrate that cancer cachexia promotes muscle EcSOD protein expression via muscle-derived IL-1β-dependent stimulation of the NBR1-p62-Nrf2 signalling pathway. These results provide further evidence for the potential therapeutic targeting of the NBR1-p62-Nrf2 signalling pathway downstream of IL-1β to mitigate cancer cachexia-induced muscle atrophy.
氧化应激会导致癌症恶病质患者的骨骼肌质量和功能丧失。然而，内源性抗氧化防御系统的改善可能减轻这种后果。在这里，我们使用已建立的Lewis 肺癌（LLC）诱导的氧化应激性肌肉萎缩模型，在 13 周龄雄性 C57BL/6J 小鼠中，证明了在外源易感性伸肌中，细胞外超氧化物歧化酶（EcSOD）水平增加。 LLC 移植显著增加了伸肌肌纤维中白细胞介素-1β（IL-1β）的表达和释放。此外，IL-1β处理 C2C12 肌管增加了 NBR1、p62 在 Ser351 处的磷酸化、Nrf2 核易位和 EcSOD 蛋白表达。体内的进一步研究表明，肌肉内注射 IL-1β足以刺激 EcSOD 表达，而肌肉特异性敲除 p62 和 Nrf2（即 p62 skmKO 和 Nrf2 skmKO 小鼠）则可以阻止这种表达。最后，由于循环中 IL-1β的增加可能导致不良后果，我们证明靶向 p62 途径足以以 Nrf2 依赖的方式驱动肌肉 EcSOD 表达。总之，癌症恶病质通过肌肉源性 IL-1β诱导的 p62 磷酸化和 Nrf2 激活增加伸肌 EcSOD 表达。这些发现为 p62 和 Nrf2 治疗癌症恶病质诱导的肌肉萎缩提供了进一步的机制证据。关键点：氧化应激在癌症恶病质期间的肌肉萎缩中起重要作用。 EcSOD 在氧化应激期间减轻肌肉损失，在癌症恶病质期间，13 周龄雄性 C57BL/6J 小鼠的伸肌 EcSOD 增加。使用小鼠和细胞模型，我们证明癌症恶病质通过肌肉源性 IL-1β依赖性刺激 NBR1-p62-Nrf2 信号通路促进肌肉 EcSOD 蛋白表达。这些结果为下游靶向 IL-1β 的 NBR1-p62-Nrf2 信号通路的潜在治疗靶点提供了进一步证据，以减轻癌症恶病质诱导的肌肉萎缩。
