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

Jason Sadek,Sergio Di Marco,Derek T Hall,Marco Emilio Bianchi,Virginie Sanguin‐Gendreau,Bianca Colalillo,Imed‐Eddine Gallouzi,William Muller,Anne‐Marie K Tremblay,Amr Omer

doi:10.15252/emmm.202013591

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.

Highlights

Cachexia is a debilitating wasting syndrome that arises in numerous chronic conditions such as cancer, chronic obstructive pulmonary disorder (COPD), chronic heart failure (CHF), HIV infection, and sepsis (Farkas et al, 2013)
We demonstrate that the Inducible nitric oxide synthase (iNOS)/nitric oxide (NO) pathway is a trigger of the metabolome derangement, mitochondrial dysfunction, and energy crisis associated with the onset of inflammation-induced muscle wasting
Since pathological production of NO by iNOS has been linked to metabolic dysfunction in inflammatory diseases (Anavi & Tirosh, 2019), we tested whether this can be the case in mouse models of inflammation-induced muscle loss

Summary

Introduction

Cachexia is a debilitating wasting syndrome that arises in numerous chronic conditions such as cancer, chronic obstructive pulmonary disorder (COPD), chronic heart failure (CHF), HIV infection, and sepsis (Farkas et al, 2013) It is characterized by a dramatic, involuntary loss of both lean muscle and adipose tissue mass (Fearon et al, 2011; Blum et al, 2014). Monotherapies targeting various cytokines have not successfully treated the condition due to its multifactorial nature (Jatoi et al, 2007; Wiedenmann et al, 2008; Jatoi et al, 2010) Downstream effectors of these pro-inflammatory cytokines within affected tissues, represent a more viable avenue for the development of effective therapies

Methods

Results

Conclusion