Publication:
Tumour-induced alterations in single-nucleus transcriptome of atrophying muscles indicate enhanced protein degradation and reduced oxidative metabolism

dc.contributor.coauthorDag, Meric
dc.contributor.coauthorDogan, Sukru Anil
dc.contributor.departmentDepartment of Molecular Biology and Genetics
dc.contributor.departmentGraduate School of Sciences and Engineering
dc.contributor.kuauthorAğca, Samet
dc.contributor.kuauthorBilgiç, Şevval Nur
dc.contributor.kuauthorKır, Serkan
dc.contributor.kuauthorSucuoğlu, Melis
dc.contributor.kuauthorWaraich, Aylin Domaniku
dc.contributor.schoolcollegeinstituteCollege of Sciences
dc.contributor.schoolcollegeinstituteGRADUATE SCHOOL OF SCIENCES AND ENGINEERING
dc.date.accessioned2024-12-29T09:40:13Z
dc.date.issued2024
dc.description.abstractBackground Tumour-induced skeletal muscle wasting in the context of cancer cachexia is a condition with profound implications for patient survival. The loss of muscle mass is a significant clinical obstacle and is linked to reduced tolerance to chemotherapy and increased frailty. Understanding the molecular mechanisms driving muscle atrophy is crucial for the design of new therapeutics.MethodsLewis lung carcinoma tumours were utilized to induce cachexia and muscle atrophy in mice. Single-nucleus libraries of the tibialis anterior (TA) muscle from tumour-bearing mice and their non-tumour-bearing controls were constructed using 10X Genomics applications following the manufacturer's guidelines. RNA sequencing results were analysed with Cell Ranger software and the Seurat R package. Oxygen consumption of mitochondria isolated from TA muscle was measured using an Oroboros O2k-FluoRespirometer. Mouse primary myotubes were treated with a recombinant ectodysplasin A2 (EDA-A2) protein to activate EDA-A2 receptor (EDA2R) signalling and study changes in gene expression and oxygen consumption.Results Tumour-bearing mice were sacrificed while exhibiting moderate cachexia. Average TA muscle weight was reduced by 11% (P = 0.0207) in these mice. A total of 12 335 nuclei, comprising 6422 nuclei from the control group and 5892 nuclei from atrophying muscles, were studied. The analysis of single-nucleus transcriptomes identified distinct myonuclear gene signatures and a shift towards type IIb myonuclei. Muscle atrophy-related genes, including Atrogin1, MuRF1 and Eda2r, were upregulated in these myonuclei, emphasizing their crucial roles in muscle wasting. Gene set enrichment analysis demonstrated that EDA2R activation and tumour inoculation led to similar expression patterns in muscle cells, including the stimulation of nuclear factor-kappa B, Janus kinase-signal transducer and activator of transcription and transforming growth factor-beta pathways and the suppression of myogenesis and oxidative phosphorylation. Muscle oxidative metabolism was suppressed by both tumours and EDA2R activation.ConclusionsThis study identified tumour-induced transcriptional changes in muscle tissue at single-nucleus resolution and highlighted the negative impact of tumours on oxidative metabolism. These findings contribute to a deeper understanding of the molecular mechanisms underlying muscle wasting.
dc.description.indexedbyWOS
dc.description.indexedbyScopus
dc.description.indexedbyPubMed
dc.description.issue5
dc.description.openaccessgold
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuTÜBİTAK
dc.description.sponsorshipThis work was supported by the EMBO Installation Grant(#4162) and the Scientific and Technological Research Councilof Turkey (TUB & Idot;TAK) Grant 122Z163 to S. Kir.
dc.description.volume15
dc.identifier.doi10.1002/jcsm.13540
dc.identifier.eissn2190-6009
dc.identifier.issn2190-5991
dc.identifier.quartileQ1
dc.identifier.scopus2-s2.0-85198416644
dc.identifier.urihttps://doi.org/10.1002/jcsm.13540
dc.identifier.urihttps://hdl.handle.net/20.500.14288/23255
dc.identifier.wos1266816600001
dc.keywordsCancer cachexia
dc.keywordsEDA2R signalling
dc.keywordsSingle-nucleus RNA sequencing
dc.keywordsSkeletal muscle atrophy
dc.language.isoeng
dc.publisherWiley
dc.relation.ispartofJournal of Cachexia, Sarcopenia and Muscle
dc.subjectGeriatrics and gerontology
dc.subjectMedicine, general and internal
dc.titleTumour-induced alterations in single-nucleus transcriptome of atrophying muscles indicate enhanced protein degradation and reduced oxidative metabolism
dc.typeJournal Article
dc.type.otherEarly access
dspace.entity.typePublication
local.contributor.kuauthorAğca, Samet
local.contributor.kuauthorWaraich, Aylin Domaniku
local.contributor.kuauthorBilgiç, Şevval Nur
local.contributor.kuauthorSucuoğlu, Melis
local.contributor.kuauthorKır, Serkan
local.publication.orgunit1GRADUATE SCHOOL OF SCIENCES AND ENGINEERING
local.publication.orgunit1College of Sciences
local.publication.orgunit2Department of Molecular Biology and Genetics
local.publication.orgunit2Graduate School of Sciences and Engineering
relation.isOrgUnitOfPublicationaee2d329-aabe-4b58-ba67-09dbf8575547
relation.isOrgUnitOfPublication3fc31c89-e803-4eb1-af6b-6258bc42c3d8
relation.isOrgUnitOfPublication.latestForDiscoveryaee2d329-aabe-4b58-ba67-09dbf8575547
relation.isParentOrgUnitOfPublicationaf0395b0-7219-4165-a909-7016fa30932d
relation.isParentOrgUnitOfPublication434c9663-2b11-4e66-9399-c863e2ebae43
relation.isParentOrgUnitOfPublication.latestForDiscoveryaf0395b0-7219-4165-a909-7016fa30932d

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
IR04798.pdf
Size:
10.02 MB
Format:
Adobe Portable Document Format