Pharmacological or genetic inhibition of iNOS prevents cachexia-mediated muscle wasting and its associated metabolism defects
Hall, Derek T
Tremblay, Anne-Marie K
Di Marco, Sergio
Bianchi, Marco Emilio
KAUST DepartmentKAUST Smart-Health Initiative and Biological and Environmental Science and Engineering (BESE) Division King Abdullah University of Science and Technology (KAUST) Jeddah Saudi Arabia
Online Publication Date2021-06-07
Print Publication Date2021-07-07
Permanent link to this recordhttp://hdl.handle.net/10754/669480
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AbstractCachexia 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.
CitationSadek, J., Hall, D. T., Colalillo, B., Omer, A., Tremblay, A. K., Sanguin-Gendreau, V., … Gallouzi, I. (2021). Pharmacological or genetic inhibition of iNOS prevents cachexia-mediated muscle wasting and its associated metabolism defects. EMBO Molecular Medicine. doi:10.15252/emmm.202013591
SponsorsWe are thankful to Shawn McGuirk for his help in understanding the intricacies of bioenergetic profiling. This work was funded by a CIHR operating grant (MOP-142399) and a CIHR project grant (PJT-159618) to IEG. DTH was funded by and a recipient of the James O. & Maria Meadows Studentship, the Maysie MacSporran Award, and the Charlotte and Leo Karassik Foundation Oncology PhD Fellowship. JS was funded by CIHR Studentship Award (GSD-164154).
JournalEMBO Molecular Medicine
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