Open AccessPharmacological or genetic inhibition of iNOS prevents cachexia‐mediated muscle wasting and its associated metabolism defects
Author(s) -
Sadek Jason,
Hall Derek T,
Colalillo Bianca,
Omer Amr,
Tremblay AnneMarie K,
SanguinGendreau Virginie,
Muller William,
Di Marco Sergio,
Bianchi Marco Emilio,
Gallouzi ImedEddine
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202013591
Subject(s) - cachexia , wasting , ampk , muscle atrophy , wasting syndrome , endocrinology , pi3k/akt/mtor pathway , inflammation , medicine , biology , skeletal muscle , phosphorylation , cancer , microbiology and biotechnology , biochemistry , apoptosis , protein kinase a
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.