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dc.contributor.authorNissinen, Tuuli
dc.contributor.authorHentilä, Jaakko
dc.contributor.authorPenna, Fabio
dc.contributor.authorLampinen, Anita
dc.contributor.authorLautaoja, Juulia
dc.contributor.authorFachada, Vasco
dc.contributor.authorHolopainen, Tanja
dc.contributor.authorRitvos, Olli
dc.contributor.authorKivelä, Riikka
dc.contributor.authorHulmi, Juha
dc.date.accessioned2018-06-11T08:32:21Z
dc.date.available2018-06-11T08:32:21Z
dc.date.issued2018
dc.identifier.citationNissinen, T., Hentilä, J., Penna, F., Lampinen, A., Lautaoja, J., Fachada, V., Holopainen, T., Ritvos, O., Kivelä, R., & Hulmi, J. (2018). Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses. <i>Journal of Cachexia, Sarcopenia and Muscle</i>, <i>9</i>(3), 514-529. <a href="https://doi.org/10.1002/jcsm.12310" target="_blank">https://doi.org/10.1002/jcsm.12310</a>
dc.identifier.otherCONVID_28041016
dc.identifier.otherTUTKAID_77578
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/58489
dc.description.abstractBackground Cancer cachexia increases morbidity and mortality, and blocking of activin receptor ligands has improved survival in experimental cancer. However, the underlying mechanisms have not yet been fully uncovered. Methods The effects of blocking activin receptor type 2 (ACVR2) ligands on both muscle and non‐muscle tissues were investigated in a preclinical model of cancer cachexia using a recombinant soluble ACVR2B (sACVR2B‐Fc). Treatment with sACVR2B‐Fc was applied either only before the tumour formation or with continued treatment both before and after tumour formation. The potential roles of muscle and non‐muscle tissues in cancer cachexia were investigated in order to understand the possible mechanisms of improved survival mediated by ACVR2 ligand blocking. Results Blocking of ACVR2 ligands improved survival in tumour‐bearing mice only when the mice were treated both before and after the tumour formation. This occurred without effects on tumour growth, production of pro‐inflammatory cytokines or the level of physical activity. ACVR2 ligand blocking was associated with increased muscle (limb and diaphragm) mass and attenuation of both hepatic protein synthesis and splenomegaly. Especially, the effects on the liver and the spleen were observed independent of the treatment protocol. The prevention of splenomegaly by sACVR2B‐Fc was not explained by decreased markers of myeloid‐derived suppressor cells. Decreased tibialis anterior, diaphragm, and heart protein synthesis were observed in cachectic mice. This was associated with decreased mechanistic target of rapamycin (mTOR) colocalization with late‐endosomes/lysosomes, which correlated with cachexia and reduced muscle protein synthesis. Conclusions The prolonged survival with continued ACVR2 ligand blocking could potentially be attributed in part to the maintenance of limb and respiratory muscle mass, but many observed non‐muscle effects suggest that the effect may be more complex than previously thought. Our novel finding showing decreased mTOR localization in skeletal muscle with lysosomes/late‐endosomes in cancer opens up new research questions and possible treatment options for cachexia.fi
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherWiley
dc.relation.ispartofseriesJournal of Cachexia, Sarcopenia and Muscle
dc.rightsCC BY-NC 4.0
dc.subject.otheractivin
dc.subject.othermyostatin
dc.subject.otherMDSC
dc.subject.otherprotein synthesis
dc.subject.otheracute phase response
dc.subject.otherphysical activity
dc.titleTreating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-201806073097
dc.contributor.laitosLiikuntatieteellinen tiedekuntafi
dc.contributor.laitosFaculty of Sport and Health Sciencesen
dc.contributor.oppiaineLiikuntafysiologiafi
dc.contributor.oppiaineExercise Physiologyen
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.date.updated2018-06-07T12:15:07Z
dc.description.reviewstatuspeerReviewed
dc.format.pagerange514-529
dc.relation.issn2190-5991
dc.relation.numberinseries3
dc.relation.volume9
dc.type.versionpublishedVersion
dc.rights.copyright© 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders
dc.rights.accesslevelopenAccessfi
dc.relation.grantnumber275922
dc.subject.ysoproteiinit
dc.subject.ysolihassurkastumasairaudet
dc.subject.ysosyöpätaudit
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p4332
jyx.subject.urihttp://www.yso.fi/onto/yso/p15977
jyx.subject.urihttp://www.yso.fi/onto/yso/p678
dc.rights.urlhttps://creativecommons.org/licenses/by-nc/4.0/
dc.relation.doi10.1002/jcsm.12310
dc.relation.funderSuomen Akatemiafi
dc.relation.funderAcademy of Finlanden
jyx.fundingprogramAkatemiatutkijan tehtävä, SAfi
jyx.fundingprogramResearch post as Academy Research Fellow, AoFen
jyx.fundinginformationThis work was supported by the Academy of Finland [grant No. 275922 (JJH) and 297245 (RK)], Cancer Society of Finland (JJH), and Jenny and Antti Wihuri Foundation (TAN, RK). We also thank Dr Philippe Pierre for kindly providing the anti‐puromycin antibody. We acknowledge Arja Pasternack, Mika Silvennoinen, Maarit Lehti, Sanna Lensu, Sira Karvinen, Mervi Matero, Jouni Härkönen, Aila Ollikainen, Risto Puurtinen, Kaisa‐Leena Tulla, Eliisa Kiukkanen, Minna Savela, and Jouni Tukiainen for their valuable help and technical assistance.


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