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dc.contributor.authorHulmi, J.
dc.contributor.authorPenna, F.
dc.contributor.authorPöllänen, N.
dc.contributor.authorNissinen, T.
dc.contributor.authorHentilä, J.
dc.contributor.authorEuro, L.
dc.contributor.authorLautaoja, J.
dc.contributor.authorBallarò, R.
dc.contributor.authorSoliymani, R.
dc.contributor.authorBaumann, M.
dc.contributor.authorRitvos, O.
dc.contributor.authorPirinen, E.
dc.contributor.authorLalowski, M.
dc.date.accessioned2020-07-17T05:42:17Z
dc.date.available2020-07-17T05:42:17Z
dc.date.issued2020
dc.identifier.citationHulmi, J., Penna, F., Pöllänen, N., Nissinen, T., Hentilä, J., Euro, L., Lautaoja, J., Ballarò, R., Soliymani, R., Baumann, M., Ritvos, O., Pirinen, E., & Lalowski, M. (2020). Muscle NAD+ depletion and Serpina3n as molecular determinants of murine cancer cachexia : the effects of blocking myostatin and activins. <i>Molecular Metabolism</i>, <i>41</i>, 101046. <a href="https://doi.org/10.1016/j.molmet.2020.101046" target="_blank">https://doi.org/10.1016/j.molmet.2020.101046</a>
dc.identifier.otherCONVID_36253945
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/71196
dc.description.abstractObjective Cancer cachexia and muscle loss are associated with increased morbidity and mortality. In preclinical animal models, blocking activin receptor (ACVR) ligands has improved survival and prevented muscle wasting in cancer cachexia without an effect on tumour growth. However, the underlying mechanisms are poorly understood. The present study aimed to identify cancer cachexia and soluble ACVR (sACVR) administration-evoked changes in muscle proteome. Methods Healthy and C26 tumour-bearing (TB) mice were treated with recombinant sACVR. The sACVR or PBS control were administered either prior to the tumour formation or by continued administration before and after tumour formation. Muscles were analysed by quantitative proteomics with further examination of mitochondria and nicotinamide adenine dinucleotide (NAD+) metabolism. To complement the first prophylactic experiment, sACVR (or PBS) was injected as a treatment following tumour cell inoculation. Results Muscle proteomics in TB cachectic mice revealed downregulated signatures for mitochondrial oxidative phosphorylation (OXPHOS) and increased acute phase response (APR). These were accompanied by muscle NAD+ deficiency, alterations in NAD+ biosynthesis including downregulation of nicotinamide riboside kinase 2 (Nrk2), and decreased muscle protein synthesis. The disturbances in NAD+ metabolism and protein synthesis were rescued upon treatment with sACVR. Across the whole proteome and APR in particular, Serpina3n represented the most upregulated protein and the strongest predictor of cachexia. However, the increase in Serpina3n expression associated with increased inflammation rather than decreased muscle mass and/or protein synthesis. Conclusions We present here an evidence implicating disturbed muscle mitochondrial OXPHOS proteome and NAD+ homeostasis in experimental cancer cachexia. Treatment of tumour-bearing mice with a blocker of activin receptor ligands restores depleted muscle NAD+ and Nrk2 as well as decreased muscle protein synthesis. These results point out putative new treatment therapies for cachexia. Our results also reveal that although acute phase protein Serpina3n may serve as a predictor of cachexia, it more likely reflects a condition of elevated inflammation.en
dc.format.mimetypeapplication/pdf
dc.languageeng
dc.language.isoeng
dc.publisherElsevier
dc.relation.ispartofseriesMolecular Metabolism
dc.rightsCC BY 4.0
dc.subject.othercancer cachexia
dc.subject.otheractivin receptor
dc.subject.otherNrk2
dc.subject.otherAPR
dc.subject.otherOXPHOS
dc.titleMuscle NAD+ depletion and Serpina3n as molecular determinants of murine cancer cachexia : the effects of blocking myostatin and activins
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-202007175351
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.type.coarhttp://purl.org/coar/resource_type/c_2df8fbb1
dc.description.reviewstatuspeerReviewed
dc.format.pagerange101046
dc.relation.issn2212-8778
dc.relation.volume41
dc.type.versionpublishedVersion
dc.rights.copyright© 2020 The Authors. Published by Elsevier GmbH
dc.rights.accesslevelopenAccessfi
dc.relation.grantnumber275922
dc.subject.ysolihassolut
dc.subject.ysosyöpätaudit
dc.subject.ysolihassurkastumasairaudet
dc.subject.ysoaineenvaihdunta
dc.subject.ysoproteiinit
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p25540
jyx.subject.urihttp://www.yso.fi/onto/yso/p678
jyx.subject.urihttp://www.yso.fi/onto/yso/p15977
jyx.subject.urihttp://www.yso.fi/onto/yso/p3066
jyx.subject.urihttp://www.yso.fi/onto/yso/p4332
dc.rights.urlhttps://creativecommons.org/licenses/by/4.0/
dc.relation.doi10.1016/j.molmet.2020.101046
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 No. 275922 to JJH and 286359 to EP) and Cancer Society of Finland to JJH. The research leading to these results has also received funding from AIRC under IG 2018 - ID. 21963 project (FP).
dc.type.okmA1


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