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dc.contributor.authorHentilä, Jaakko
dc.contributor.authorNissinen, Tuuli
dc.contributor.authorKorkmaz, Ayhan
dc.contributor.authorLensu, Sanna
dc.contributor.authorSilvennoinen, Mika
dc.contributor.authorPasternack, Arja
dc.contributor.authorRitvos, Olli
dc.contributor.authorAtalay, Mustafa
dc.contributor.authorHulmi, Juha
dc.date.accessioned2019-02-14T08:39:38Z
dc.date.available2019-02-14T08:39:38Z
dc.date.issued2019fi
dc.identifier.citationHentilä, J., Nissinen, T., Korkmaz, A., Lensu, S., Silvennoinen, M., Pasternack, A., . . . Hulmi, J. (2019). Activin Receptor Ligand Blocking and Cancer Have Distinct Effects on Protein and Redox Homeostasis in Skeletal Muscle and Liver. <em>Frontiers in Physiology</em>, 9, 1917. <a href="https://doi.org/10.3389/fphys.2018.01917">doi:10.3389/fphys.2018.01917</a>fi
dc.identifier.otherTUTKAID_80310
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/62775
dc.description.abstractMuscle wasting in cancer cachexia can be alleviated by blocking activin receptor type 2 (ACVR2) ligands through changes in protein synthesis/degradation. These changes in cellular and protein metabolism may alter protein homeostasis. First, we elucidated the acute (1–2 days) and 2-week effects of blocking ACVR2 ligands by soluble activin receptor 2B (sACVR2B-Fc) on unfolded protein response (UPR), heat shock proteins (HSPs) and redox balance in a healthy mouse skeletal muscle. Second, we examined UPR, autophagy and redox balance with or without sACVR2B-Fc administration in muscle and liver of C26 tumor-bearing mice. The indicators of UPR and HSPs were not altered 1–2 days after a single sACVR2B-Fc administration in healthy muscles, but protein carbonyls increased (p < 0.05). Two weeks of sACVR2B-Fc administration increased muscle size, which was accompanied by increased UPR markers: GRP78 (p < 0.05), phosphorylated eIF2α (p < 0.01) and HSP47 (p < 0.01). Additionally, protein carbonyls and reduced form of glutathione increased (GSH) (p < 0.05). On the other hand, C26 cancer cachexia manifested decreased UPR markers (p-eIF2α, HSP47, p-JNK; p < 0.05) and antioxidant GSH (p < 0.001) in muscle, whereas the ratio of oxidized to reduced glutathione increased (GSSG/GSH; p < 0.001). Administration of sACVR2B-Fc prevented the decline in GSH and increased some of the UPR indicators in tumor-bearing mice. Additionally, autophagy markers LC3II/I (p < 0.05), Beclin-1 (p < 0.01), and P62 (p < 0.05) increased in the skeletal muscle of tumor-bearing mice. Finally, indicators of UPR, PERK, p-eIF2α and GRP78, increased (p < 0.05), whereas ATF4 was strongly decreased (p < 0.01) in the liver of tumor-bearing mice while sACVR2B-Fc had no effect. Muscle GSH and many of the altered UPR indicators correlated with tumor mass, fat mass and body mass loss. In conclusion, experimental cancer cachexia is accompanied by distinct and tissue-specific changes in proteostasis. Muscle hypertrophy induced by blocking ACVR2B ligands may be accompanied by the induction of UPR and increased protein carbonyls but blocking ACVR2B ligands may upregulate antioxidant protection.fi
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherFrontiers Research Foundation
dc.relation.ispartofseriesFrontiers in Physiology
dc.rightsCC BY 4.0
dc.subject.othersyöpätauditfi
dc.subject.otherlihassurkastumasairaudetfi
dc.subject.otherproteiinitfi
dc.subject.otherlihaksetfi
dc.subject.othermaksafi
dc.subject.otheroksidatiivinen stressifi
dc.subject.othercancer cachexiafi
dc.subject.otherautophagyfi
dc.subject.othermyostatinfi
dc.subject.otheractivinfi
dc.subject.otherliverfi
dc.subject.otherskeletal musclefi
dc.subject.otherunfolded protein responsefi
dc.subject.otherglutathionefi
dc.subject.otheroxidative stress/redoxfi
dc.titleActivin Receptor Ligand Blocking and Cancer Have Distinct Effects on Protein and Redox Homeostasis in Skeletal Muscle and Liverfi
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-201902071462
dc.contributor.laitosLiikuntatieteellinen tiedekuntafi
dc.contributor.laitosFaculty of Sport and Health Sciencesen
dc.contributor.oppiaineLiikuntafysiologia
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.date.updated2019-02-07T16:15:13Z
dc.description.reviewstatuspeerReviewed
dc.relation.issn1664-042X
dc.relation.numberinseries0
dc.relation.volume9
dc.type.versionpublishedVersion
dc.rights.copyright© 2019 Hentilä, Nissinen, Korkmaz, Lensu, Silvennoinen, Pasternack, Ritvos, Atalay and Hulmi.
dc.rights.accesslevelopenAccessfi
dc.format.contentfulltext
dc.rights.urlhttps://creativecommons.org/licenses/by/4.0/
dc.relation.doi10.3389/fphys.2018.01917


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