Pharmacological or genetic inhibition of iNOS prevents cachexia‐mediated muscle wasting and its associated metabolism defects

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.

Metabolomics and its Applications in Cancer Cachexia

“…jp/), The Kyoto Encyclopedia of Genes and Genomes (KEGG; https://www.genome.jp/kegg/), and software such as MetaboAnalyst 5.0 (https://www.metaboanalyst.ca/) (Pang et al, 2021). A growing number of studies have been using MetaboAnalyst website to conduct the pathway analysis and ROC analysis in CC studies (Yang et al, 2018;Cui et al, 2019b;Sadek et al, 2021).…”

“…Increased expressions of inducible nitric oxide synthase (iNOS) have been observed in muscle tissues of cancer, AIDS, chronic heart failure, and COPD cachexia patients, suggesting that iNOS may be involved in the onset of cachexia under various conditions (Adams et al, 2003;Agusti et al, 2004;Ramamoorthy et al, 2009). Sadek and colleagues identified a signature of amino acids that were altered by iNOS activity in muscle by performing LC-MS-based and GC-MS-based metabolomic analyses based on the C26 murine model (Sadek et al, 2021). Notably, iNOS could significantly increase levels of arginine, lysine, tryptophan and methylhistidine, which could be decreased by inhibiting iNOS.…”

CD155 is essential for skeletal muscle regeneration by regulating satellite cell proliferation and differentiation

“…The treatment of muscle regeneration after an extensive injury has always been difficult. Many studies have shown a close link between muscle regeneration and immunity 30,31 . Those studies suggested that the regeneration process is traditionally divided into two parts: proinflammatory and anti‐inflammatory restorative phases, and the regeneration can be regulated by controlling the shift of the two phases 6 .…”

Molecular mechanisms of cancer cachexia‐related loss of skeletal muscle mass: data analysis from preclinical and clinical studies

“…However, the pharmacological inhibition of NF‐κB has proven its efficiency in cancer cachectic animals 27 . Besides, selective pharmacological inhibition of iNOS, which is a downstream effector of NF‐κB pathway and is highly expressed in cachectic muscle, 120 ameliorates cancer cachexia in mouse 120 …”

“…27 Besides, selective pharmacological inhibition of iNOS, which is a downstream effector of NF-κB pathway and is highly expressed in cachectic muscle, 120 ameliorates cancer cachexia in mouse. 120…”