Cachexia syndrome develops in patients with diseases such as cancer and sepsis and is characterized by progressive muscle wasting. While iNOS is one of the main effectors of cachexia, its mechanism of action and whether it could be targeted for therapy remains unexplored. Here, we show that iNOS knockout mice and mice treated with the clinically tested iNOS inhibitor GW274150 are protected against muscle wasting in models of both septic and cancer cachexia. We demonstrate that iNOS triggers muscle wasting by disrupting mitochondrial content, morphology, and energy production processes such as the TCA cycle and acylcarnitine transport. Notably, iNOS inhibits oxidative phosphorylation through impairment of complexes II and IV of the electron transport chain and reduces ATP production, leading to energetic stress, activation of AMPK, suppression of mTOR, and, ultimately, muscle atrophy. Importantly, all these effects were reversed by GW274150. Therefore, our data establish how iNOS induces muscle wasting under cachectic conditions and provide a proof of principle for the repurposing of iNOS inhibitors, such as GW274150 for the treatment of cachexia.

中文翻译：

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iNOS 的药理学或基因抑制可预防恶病质介导的肌肉萎缩及其相关代谢缺陷

恶病质综合征发生在患有癌症和败血症等疾病的患者中，其特征是进行性肌肉萎缩。虽然 iNOS 是恶病质的主要效应因子之一，但其作用机制以及是否可以作为治疗靶点仍有待探索。在这里，我们证明 iNOS 敲除小鼠和经过临床测试的 iNOS 抑制剂 GW274150 治疗的小鼠在脓毒症和癌症恶病质模型中都可以防止肌肉萎缩。我们证明 iNOS 通过破坏线粒体含量、形态和能量产生过程（例如 TCA 循环和酰基肉碱运输）来引发肌肉萎缩。值得注意的是，iNOS 通过损害电子传递链的复合物 II 和 IV 来抑制氧化磷酸化，并减少 ATP 的产生，从而导致能量应激、AMPK 激活、mTOR 抑制，并最终导致肌肉萎缩。重要的是，所有这些影响都被 GW274150 逆转了。因此，我们的数据确定了 iNOS 如何在恶病质条件下诱导肌肉萎缩，并为重新利用 iNOS 抑制剂（例如用于治疗恶病质的 GW274150）提供原理证明。