Pharmacological or genetic inhibition of iNOS prevents cachexia‐mediated muscle wasting and its associated metabolism defects. Issue 7 (7th June 2021) - Sadek, Jason
Abstract: 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. Synopsis: Cachexia is a condition marked by severe skeletal muscle atrophy in patients affected by diseases such as cancer or sepsis. The inflammation‐induced factor inducible nitric oxide synthase (iNOS) was found to promote muscle wasting by causing mitochondrial dysfunction and energetic stress. In an LPS‐induced model of septic cachexia, muscle wasting was prevented by iNOS impairment through genetic knockout or use of the pharmacological inhibitor GW274150. Muscle wasting was prevented by GW274150 in the C26 adenocarcinoma‐induced model of cancer cachexia. Metabolic processes, including glycolysis, the TCA cycle, acylcarnitine metabolism, and oxidative phosphorylation were dysregulated by iNOS. Cachexia‐induced loss of mitochondrial structure and content in skeletal muscle was prevented by iNOS inhibition. Abstract : Cachexia is a condition marked by severe skeletal muscle atrophy in patients affected by diseases such as cancer or sepsis. The inflammation‐induced factor inducible nitric oxide synthase (iNOS) was found to promote muscle wasting by causing mitochondrial dysfunction and energetic stress.