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dc.contributor.authorHulmi, Juha
dc.contributor.authorNissinen, Tuuli
dc.contributor.authorRäsänen, Markus
dc.contributor.authorDegerman, Joni
dc.contributor.authorLautaoja, Juulia
dc.contributor.authorHemanthakumar, Karthik Amudhala
dc.contributor.authorBackman, Janne T.
dc.contributor.authorRitvos, Olli
dc.contributor.authorSilvennoinen, Mika
dc.contributor.authorKivelä, Riikka
dc.date.accessioned2018-04-19T09:29:07Z
dc.date.available2018-04-19T09:29:07Z
dc.date.issued2018
dc.identifier.citationHulmi, J., Nissinen, T., Räsänen, M., Degerman, J., Lautaoja, J., Hemanthakumar, K. A., Backman, J. T., Ritvos, O., Silvennoinen, M., & Kivelä, R. (2018). Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle. <i>Journal of Cachexia, Sarcopenia and Muscle</i>, <i>9</i>(2), 417-432. <a href="https://doi.org/10.1002/jcsm.12265" target="_blank">https://doi.org/10.1002/jcsm.12265</a>
dc.identifier.otherCONVID_27415815
dc.identifier.otherTUTKAID_76036
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/57702
dc.description.abstractBackground Toxicity of chemotherapy on skeletal muscles and the heart may significantly contribute to cancer cachexia, mortality, and decreased quality of life. Doxorubicin (DOX) is an effective cytostatic agent, which unfortunately has toxic effects on many healthy tissues. Blocking of activin receptor type IIB (ACVR2B) ligands is an often used strategy to prevent skeletal muscle loss, but its effects on the heart are relatively unknown. Methods The effects of DOX treatment with or without pre-treatment with soluble ACVR2B-Fc (sACVR2B-Fc) were investigated. The mice were randomly assigned into one of the three groups: (1) vehicle (PBS)-treated controls, (2) DOX-treated mice (DOX), and (3) DOX-treated mice administered with sACVR2B-Fc during the experiment (DOX + sACVR2B-Fc). DOX was administered with a cumulative dose of 24 mg/kg during 2 weeks to investigate cachexia outcome in the heart and skeletal muscle. To understand similarities and differences between skeletal and cardiac muscles in their responses to chemotherapy, the tissues were collected 20 h after a single DOX (15 mg/kg) injection and analysed with genome-wide transcriptomics and mRNA and protein analyses. The combination group was pre-treated with sACVR2B-Fc 48 h before DOX administration. Major findings were also studied in mice receiving only sACVR2B-Fc. Results The DOX treatment induced similar (~10%) wasting in skeletal muscle and the heart. However, transcriptional changes in response to DOX were much greater in skeletal muscle. Pathway analysis and unbiased transcription factor analysis showed that p53-p21-REDD1 is the main common pathway activated by DOX in both skeletal and cardiac muscles. These changes were attenuated by blocking ACVR2B ligands especially in skeletal muscle. Tceal7 (3-fold to 5-fold increase), transferrin receptor (1.5-fold increase), and Ccl21 (0.6-fold to 0.9-fold decrease) were identified as novel genes responsive to blocking ACVR2B ligands. Overall, at the transcriptome level, ACVR2B ligand blocking had only minor influence in the heart while it had marked effects in skeletal muscle. The same was also true for the effects on tissue wasting. This may be explained in part by about 18-fold higher gene expression of myostatin in skeletal muscle compared with the heart. Conclusions Cardiac and skeletal muscles display similar atrophy after DOX treatment, but the mechanisms for this may differ between the tissues. The present results suggest that p53-p21-REDD1 signalling is the main common DOX-activated pathway in these tissues and that blocking activin receptor ligands attenuates this response, especially in skeletal muscle supporting the overall stronger effects of this treatment in skeletal muscles.
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherWiley
dc.relation.ispartofseriesJournal of Cachexia, Sarcopenia and Muscle
dc.subject.othermyostatin
dc.subject.otheractivins
dc.subject.otherdoxorubicin
dc.titlePrevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-201804091955
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.updated2018-04-09T06:06:19Z
dc.type.coarhttp://purl.org/coar/resource_type/c_2df8fbb1
dc.description.reviewstatuspeerReviewed
dc.format.pagerange417-432
dc.relation.issn2190-5991
dc.relation.numberinseries2
dc.relation.volume9
dc.type.versionpublishedVersion
dc.rights.copyright© 2017 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License.
dc.rights.accesslevelopenAccessfi
dc.relation.grantnumber275922
dc.subject.ysosytostaattihoito
dc.subject.ysoproteiinit
dc.subject.ysolihassurkastumasairaudet
dc.subject.ysotranskriptomi
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p9994
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/p38915
dc.rights.urlhttps://creativecommons.org/licenses/by-nc/4.0/
dc.relation.doi10.1002/jcsm.12265
dc.relation.funderSuomen Akatemiafi
dc.relation.funderResearch Council of Finlanden
jyx.fundingprogramAkatemiatutkija, SAfi
jyx.fundingprogramAcademy Research Fellow, AoFen
jyx.fundinginformationThis work was supported by the Academy of Finland (grant nos. 275922 and 297245) and Jenny and Antti Wihuri Foundation.
dc.type.okmA1


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© 2017 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License.
Except where otherwise noted, this item's license is described as © 2017 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License.