{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T14:05:06Z","timestamp":1790431506133,"version":"4.1.0"},"reference-count":67,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2017,12,11]],"date-time":"2017-12-11T00:00:00Z","timestamp":1512950400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004022","name":"Jenny ja Antti Wihurin Rahasto","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004022","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["297245"],"award-info":[{"award-number":["297245"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["275922"],"award-info":[{"award-number":["275922"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The effects of DOX treatment with or without pre\u2010treatment with soluble ACVR2B\u2010Fc (sACVR2B\u2010Fc) were investigated. The mice were randomly assigned into one of the three groups: (1) vehicle (PBS)\u2010treated controls, (2) DOX\u2010treated mice (DOX), and (3) DOX\u2010treated mice administered with sACVR2B\u2010Fc during the experiment (DOX\u00a0+\u00a0sACVR2B\u2010Fc). DOX was administered with a cumulative dose of 24\u00a0mg\/kg during 2\u00a0weeks 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\u00a0h after a single DOX (15\u00a0mg\/kg) injection and analysed with genome\u2010wide transcriptomics and mRNA and protein analyses. The combination group was pre\u2010treated with sACVR2B\u2010Fc 48\u00a0h before DOX administration. Major findings were also studied in mice receiving only sACVR2B\u2010Fc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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\u2010p21\u2010REDD1 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\u2010fold to 5\u2010fold increase), transferrin receptor (1.5\u2010fold increase), and Ccl21 (0.6\u2010fold to 0.9\u2010fold 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\u2010fold higher gene expression of myostatin in skeletal muscle compared with the heart.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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\u2010p21\u2010REDD1 signalling is the main common DOX\u2010activated 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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12265","type":"journal-article","created":{"date-parts":[[2017,12,12]],"date-time":"2017-12-12T02:29:43Z","timestamp":1513045783000},"page":"417-432","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Prevention of chemotherapy\u2010induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle"],"prefix":"10.1002","volume":"9","author":[{"given":"Juha J.","family":"Hulmi","sequence":"first","affiliation":[{"name":"Biology of Physical Activity, Neuromuscular Research Center, Faculty of Sport and Health Sciences University of Jyv\u00e4skyl\u00e4  Jyv\u00e4skyl\u00e4 Finland"},{"name":"Department of Physiology, Faculty of Medicine University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuuli A.","family":"Nissinen","sequence":"additional","affiliation":[{"name":"Biology of Physical Activity, Neuromuscular Research Center, Faculty of Sport and Health Sciences University of Jyv\u00e4skyl\u00e4  Jyv\u00e4skyl\u00e4 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"R\u00e4s\u00e4nen","sequence":"additional","affiliation":[{"name":"Wihuri Research Institute, Helsinki, Finland and Translational Cancer Biology Program, Research Programs Unit, Faculty of Medicine University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joni","family":"Degerman","sequence":"additional","affiliation":[{"name":"Wihuri Research Institute, Helsinki, Finland and Translational Cancer Biology Program, Research Programs Unit, Faculty of Medicine University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juulia H.","family":"Lautaoja","sequence":"additional","affiliation":[{"name":"Biology of Physical Activity, Neuromuscular Research Center, Faculty of Sport and Health Sciences University of Jyv\u00e4skyl\u00e4  Jyv\u00e4skyl\u00e4 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik Amudhala","family":"Hemanthakumar","sequence":"additional","affiliation":[{"name":"Wihuri Research Institute, Helsinki, Finland and Translational Cancer Biology Program, Research Programs Unit, Faculty of Medicine University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janne T.","family":"Backman","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Faculty of Medicine University of Helsinki and Helsinki University Hospital  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olli","family":"Ritvos","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika","family":"Silvennoinen","sequence":"additional","affiliation":[{"name":"Biology of Physical Activity, Neuromuscular Research Center, Faculty of Sport and Health Sciences University of Jyv\u00e4skyl\u00e4  Jyv\u00e4skyl\u00e4 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riikka","family":"Kivel\u00e4","sequence":"additional","affiliation":[{"name":"Wihuri Research Institute, Helsinki, Finland and Translational Cancer Biology Program, Research Programs Unit, Faculty of Medicine University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,12,11]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2015.09.001"},{"key":"e_1_2_7_3_1","first-page":"288","article-title":"Ultrastructural features of Adriamycin\u2010induced skeletal and cardiac muscle toxicity","volume":"118","author":"Doroshow JH","year":"1985","journal-title":"Am J Pathol"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.11.4275"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep32695"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1616168113"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00720.2015"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2042-7158.2012.01567.x"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcha.2015.11.004"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2919"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2011.3965"},{"key":"e_1_2_7_12_1","first-page":"2023","article-title":"Characterization of the effect of in vivo doxorubicin treatment on skeletal muscle function in the rat","volume":"31","author":"Hydock DS","year":"2011","journal-title":"Anticancer Res"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2014.286518"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12015-016-9711-3"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2014.09.010"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1988.tb14068.x"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/387083a0"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-245894"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201607231"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0505996102"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00389.2012"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00223.2010"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.07.011"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29930"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.14.1812"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.882068"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00200.2011"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0023818"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-3152"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000231290.45676.d4"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2014.06.1167"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1314"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.10-168799"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-12-507"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003731"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.10-157313"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2014.10.001"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20091906"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI72931"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00832.2005"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00128.2014"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.72.1.1"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.10.10.1173"},{"key":"e_1_2_7_45_1","doi-asserted-by":"crossref","first-page":"5524","DOI":"10.1016\/S0021-9258(18)53352-4","article-title":"Antineoplastic agent doxorubicin inhibits myogenic differentiation of C2 myoblasts","volume":"268","author":"Kurabayashi M","year":"1993","journal-title":"J Biol Chem"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00706-2"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90039-X"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406879200"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.799700"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11626-014-9743-4"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.20494"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00144.2016"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.7.2283-2293.2002"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00735.2009"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0018005"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00010.2014"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033038"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0112172"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111604200"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2015.09.041"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-015-3671-z"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP272847"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.1.315"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.304185"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000120704.97934.41"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00065.2013"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.21743"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12089"}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjcsm.12265","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.12265","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T12:35:56Z","timestamp":1695558956000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.12265"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12,11]]},"references-count":67,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2018,4]]}},"alternative-id":["10.1002\/jcsm.12265"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.12265","archive":["Portico"],"relation":{},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12,11]]},"assertion":[{"value":"2017-08-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-10-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-12-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}