Pharmacological or genetic inhibition of iNOS prevents cachexia‐mediated muscle wasting and its associated metabolism defects
| Autor: | Marco Bianchi, Bianca Colalillo, Amr Omer, Sergio Di Marco, William J. Muller, Jason Sadek, Imed-Eddine Gallouzi, Anne-Marie K. Tremblay, Virginie Sanguin-Gendreau, Derek T Hall |
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| Přispěvatelé: | Sadek, J., Hall, D. T., Colalillo, B., Omer, A., Tremblay, A. -M. K., Sanguin-Gendreau, V., Muller, W., Di Marco, S., Bianchi, M. E., Gallouzi, I. -E. |
| Rok vydání: | 2021 |
| Předmět: |
Cachexia
Inflammation Oxidative phosphorylation Article Mice 03 medical and health sciences 0302 clinical medicine Neoplasms medicine cancer Animals Humans Musculoskeletal System Wasting PI3K/AKT/mTOR pathway 030304 developmental biology 0303 health sciences business.industry Muscles AMPK Articles medicine.disease Muscle atrophy Mitochondria 3. Good health iNOS Muscular Atrophy inflammation 030220 oncology & carcinogenesis Knockout mouse Cancer research Molecular Medicine medicine.symptom business metabolism |
| Zdroj: | EMBO Molecular Medicine |
| ISSN: | 1757-4684 1757-4676 |
| DOI: | 10.15252/emmm.202013591 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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