Muscle NAD+ depletion and Serpina3n as molecular determinants of murine cancer cachexia – the effects of blocking myostatin and activins

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dc.contributor.author Hulmi, Juha J.
dc.contributor.author Penna, Fabio
dc.contributor.author Pöllänen, Noora
dc.contributor.author Nissinen, Tuuli A.
dc.contributor.author Hentila, Jaakko
dc.contributor.author Euro, Liliya
dc.contributor.author Lautaoja, Juulia H.
dc.contributor.author Ballarò, Riccardo
dc.contributor.author Soliymani, Rabah
dc.contributor.author Baumann, Marc
dc.contributor.author Ritvos, Olli
dc.contributor.author Pirinen, Eija
dc.contributor.author Lalowski, Maciej
dc.date.accessioned 2020-09-01T07:31:03Z
dc.date.available 2020-09-01T07:31:03Z
dc.date.issued 2020-11
dc.identifier.citation Hulmi , J J , Penna , F , Pöllänen , N , Nissinen , T A , Hentila , J , Euro , L , Lautaoja , J H , 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 ' , Molecular metabolism , vol. 41 , 101046 . https://doi.org/10.1016/j.molmet.2020.101046
dc.identifier.other PURE: 139614590
dc.identifier.other PURE UUID: 706e9a16-d1c5-4523-b664-b86de521a324
dc.identifier.other ORCID: /0000-0002-3683-4096/work/79877806
dc.identifier.other ORCID: /0000-0001-9705-3886/work/79880701
dc.identifier.other WOS: 000580985700006
dc.identifier.uri http://hdl.handle.net/10138/318918
dc.description.abstract Objective 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 upontreatment 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.extent 13
dc.language.iso eng
dc.relation.ispartof Molecular metabolism
dc.rights cc_by
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject 318 Medical biotechnology
dc.subject C26
dc.subject OXPHOS
dc.subject APR
dc.subject Nrk2
dc.subject Activin receptor
dc.subject Cancer cachexia
dc.subject C26
dc.subject Cancer cachexia
dc.subject Activin receptor
dc.subject Nrk2
dc.subject APR
dc.subject OXPHOS
dc.subject MUSCULAR-DYSTROPHY
dc.subject EXPRESSION
dc.subject METABOLISM
dc.subject SIRTUINS
dc.subject REVERSAL
dc.subject MICE
dc.title Muscle NAD+ depletion and Serpina3n as molecular determinants of murine cancer cachexia – the effects of blocking myostatin and activins en
dc.type Article
dc.contributor.organization CAMM - Research Program for Clinical and Molecular Metabolism
dc.contributor.organization Faculty of Medicine
dc.contributor.organization University of Helsinki
dc.contributor.organization Research Programs Unit
dc.contributor.organization STEMM - Stem Cells and Metabolism Research Program
dc.contributor.organization Department of Biochemistry and Developmental Biology
dc.contributor.organization Helsinki Institute of Life Science HiLIFE
dc.contributor.organization Marc Baumann / Principal Investigator
dc.contributor.organization University Management
dc.contributor.organization Department of Physiology
dc.contributor.organization Growth factor physiology
dc.contributor.organization Eija Pirinen / Principal Investigator
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1016/j.molmet.2020.101046
dc.relation.issn 2212-8778
dc.rights.accesslevel openAccess
dc.type.version acceptedVersion
dc.type.version publishedVersion

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