Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways

Abstract Cancer-induced cachexia, characterized by muscle wasting, is a lethal metabolic syndrome with undefined etiology. Current consensus is that multiple factors contribute to cancer-induced muscle wasting, and therefore therapy requires combinational strategies. Here, we show that Toll-like rec...

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Autores principales:	Guohua Zhang, Zhelong Liu, Hui Ding, Hongyu Miao, Jose M. Garcia, Yi-Ping Li
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ad02f855b6764ae9a516e85494dbc456
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spelling	oai:doaj.org-article:ad02f855b6764ae9a516e85494dbc4562021-12-02T15:05:52ZToll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways10.1038/s41598-017-02347-22045-2322https://doaj.org/article/ad02f855b6764ae9a516e85494dbc4562017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02347-2https://doaj.org/toc/2045-2322Abstract Cancer-induced cachexia, characterized by muscle wasting, is a lethal metabolic syndrome with undefined etiology. Current consensus is that multiple factors contribute to cancer-induced muscle wasting, and therefore therapy requires combinational strategies. Here, we show that Toll-like receptor 4 (TLR4) mediates cancer-induced muscle wasting by directly activating muscle catabolism as well as stimulating an innate immune response in mice bearing Lewis lung carcinoma (LLC), and targeting TLR4 alone effectively abrogate muscle wasting. Utilizing specific siRNAs we observed that LLC cell-conditioned medium (LCM)-treated C2C12 myotubes underwent a rapid catabolic response in a TLR4-dependent manner, including activation of the p38 MAPK−C/EBPβ signaling pathway as well as the ubiquitin-proteasome and autophagy-lysosome pathways, resulting in myotube atrophy. Utilizing a reporter cell-line it was confirmed that LCM activated TLR4. These results suggest that LLC-released cachexins directly activate muscle catabolism via activating TLR4 on muscle cells independent of immune responses. Critically, LLC tumor-bearing TLR4−/− mice were spared from muscle wasting due to a blockade in muscle catabolic pathways. Further, tumor-induced elevation of circulating TNFα and interleukin-6 (IL-6) was abolished in TLR4−/− mice. These data suggest that TLR4 is a central mediator and therapeutic target of cancer-induced muscle wasting.Guohua ZhangZhelong LiuHui DingHongyu MiaoJose M. GarciaYi-Ping LiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Guohua Zhang Zhelong Liu Hui Ding Hongyu Miao Jose M. Garcia Yi-Ping Li Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways
description	Abstract Cancer-induced cachexia, characterized by muscle wasting, is a lethal metabolic syndrome with undefined etiology. Current consensus is that multiple factors contribute to cancer-induced muscle wasting, and therefore therapy requires combinational strategies. Here, we show that Toll-like receptor 4 (TLR4) mediates cancer-induced muscle wasting by directly activating muscle catabolism as well as stimulating an innate immune response in mice bearing Lewis lung carcinoma (LLC), and targeting TLR4 alone effectively abrogate muscle wasting. Utilizing specific siRNAs we observed that LLC cell-conditioned medium (LCM)-treated C2C12 myotubes underwent a rapid catabolic response in a TLR4-dependent manner, including activation of the p38 MAPK−C/EBPβ signaling pathway as well as the ubiquitin-proteasome and autophagy-lysosome pathways, resulting in myotube atrophy. Utilizing a reporter cell-line it was confirmed that LCM activated TLR4. These results suggest that LLC-released cachexins directly activate muscle catabolism via activating TLR4 on muscle cells independent of immune responses. Critically, LLC tumor-bearing TLR4−/− mice were spared from muscle wasting due to a blockade in muscle catabolic pathways. Further, tumor-induced elevation of circulating TNFα and interleukin-6 (IL-6) was abolished in TLR4−/− mice. These data suggest that TLR4 is a central mediator and therapeutic target of cancer-induced muscle wasting.
format	article
author	Guohua Zhang Zhelong Liu Hui Ding Hongyu Miao Jose M. Garcia Yi-Ping Li
author_facet	Guohua Zhang Zhelong Liu Hui Ding Hongyu Miao Jose M. Garcia Yi-Ping Li
author_sort	Guohua Zhang
title	Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways
title_short	Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways
title_full	Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways
title_fullStr	Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways
title_full_unstemmed	Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways
title_sort	toll-like receptor 4 mediates lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ad02f855b6764ae9a516e85494dbc456
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Toll-like receptor 4 mediates Lewis lung carcinoma-induced muscle wasting via coordinate activation of protein degradation pathways

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