STAT3 promotes IFNγ/TNFα-induced muscle wasting in an NF-κB-dependent and IL-6-independent manner.

Jennifer F Ma,Anne‐Marie K Tremblay,Sergio Di Marco,Derek T Hall,Brenda J Sanchez,Imed‐Eddine Gallouzi

doi:10.15252/emmm.201607052

Jennifer F Ma, Anne‐Marie K Tremblay + Show 4 more

Open Access

https://doi.org/10.15252/emmm.201607052

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Abstract

Cachexia is a debilitating syndrome characterized by involuntary muscle wasting that is triggered at the late stage of many cancers. While the multifactorial nature of this syndrome and the implication of cytokines such as IL‐6, IFNγ, and TNFα is well established, we still do not know how various effector pathways collaborate together to trigger muscle atrophy. Here, we show that IFNγ/TNFα promotes the phosphorylation of STAT3 on Y705 residue in the cytoplasm of muscle fibers by activating JAK kinases. Unexpectedly, this effect occurs both in vitro and in vivo independently of IL‐6, which is considered as one of the main triggers of STAT3‐mediated muscle wasting. pY‐STAT3 forms a complex with NF‐κB that is rapidly imported to the nucleus where it is recruited to the promoter of the iNos gene to activate the iNOS/NO pathway, a well‐known downstream effector of IFNγ/TNFα‐induced muscle loss. Together, these findings show that STAT3 and NF‐κB respond to the same upstream signal and cooperate to promote the expression of pro‐cachectic genes, the identification of which could provide effective targets to combat this deadly syndrome.

Highlights

Cancer-related cachexia is a debilitating syndrome characterized by the progressive loss of body weight that is triggered in part by an involuntary loss of skeletal muscle mass, referred to as muscle wasting (Dodson et al, 2011; Ma et al, 2012; Argiles et al, 2016)
These observations raise the possibility that the phosphorylation of STAT3 on its Y705 residue is an integral part of the downstream signaling pathway used by IFNc/tumor necrosis factor alpha (TNFa) to trigger muscle wasting
The failure of anti-TNFa or anti-IL-6 therapies to prevent muscle wasting in humans is a clear indication that the onset of this deadly syndrome is resistant to mono-therapeutic intervention (Wiedenmann et al, 2008; Jatoi et al, 2010; Bayliss et al, 2011)

Summary

Introduction

Cancer-related cachexia is a debilitating syndrome characterized by the progressive loss of body weight that is triggered in part by an involuntary loss of skeletal muscle mass, referred to as muscle wasting (Dodson et al, 2011; Ma et al, 2012; Argiles et al, 2016). Unlike muscle atrophy caused by starvation or physical inactivity, muscle wasting in cachectic patients cannot be reversed by nutritional supplementation (Fearon, 2011; Argiles et al, 2013). There is no standard treatment option available to prevent or treat cachexia. This highlights the importance of delineating the pro-cachectic mechanism of action in order to identify targets to combat this deadly syndrome

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