{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T07:44:20Z","timestamp":1791618260377,"version":"4.3.4"},"reference-count":43,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T00:00:00Z","timestamp":1644883200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004047","name":"Karolinska Institutet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014437","name":"Wenner-Gren Stiftelserna","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014437","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":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Patients with breast cancer exhibit muscle weakness, which is associated with increased mortality risk and reduced quality of life. Muscle weakness is experienced even in the absence of loss of muscle mass in breast cancer patients, indicating intrinsic muscle dysfunction. Physical activity is correlated with reduced cancer mortality and disease recurrence. However, the molecular processes underlying breast cancer\u2010induced muscle weakness and the beneficial effect of exercise are largely unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Eight\u2010week\u2010old breast cancer (MMTV\u2010PyMT, PyMT) and control (WT) mice had access to active or inactive in\u2010cage voluntary running wheels for 4\u00a0weeks. Mice were also subjected to a treadmill test. Muscle force was measured <jats:italic>ex vivo<\/jats:italic>. Tumour markers were determined with immunohistochemistry. Mitochondrial biogenesis and function were assessed with transcriptional analyses of PGC\u20101\u03b1, the electron transport chain (ETC) and antioxidants superoxide dismutase (Sod) and catalase (Cat), combined with activity measurements of SOD, citrate synthase (CS) and \u03b2\u2010hydroxyacyl\u2010CoA\u2010dehydrogenase (\u03b2HAD). Serum and intramuscular stress levels were evaluated by enzymatic assays, immunoblotting, and transcriptional analyses of, for example, tumour necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) and p38 mitogen\u2010activated protein kinase (MAPK) signalling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PyMT mice endured shorter time and distance during the treadmill test (~30%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and <jats:italic>ex vivo<\/jats:italic> force measurements revealed ~25% weaker slow\u2010twitch soleus muscle (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). This was independent of cancer\u2010induced alteration of muscle size or fibre type. Inflammatory stressors in serum and muscle, including TNF\u2010\u03b1 and p38 MAPK, were higher in PyMT than in WT mice (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Cancer\u2010induced decreases in ETC (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and antioxidant gene expression were observed (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). The exercise intervention counteracted the cancer\u2010induced muscle weakness and was accompanied by a less aggressive, differentiated tumour phenotype, determined by increased CK8 and reduced CK14 expression (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). In PyMT mice, the exercise intervention led to higher CS activity (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.23), enhanced \u03b2\u2010HAD and SOD activities (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), and reduced levels of intramuscular stressors together with a normalization of the expression signature of TNF\u03b1\u2010targets and ETC genes (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). At the same time, the exercise\u2010induced PGC\u20101\u03b1 expression, and CS and \u03b2\u2010HAD activity was blunted in muscle from the PyMT mice as compared with WT mice, indicative that breast cancer interfere with transcriptional programming of mitochondria and that the molecular adaptation to exercise differs between healthy mice and those afflicted by disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Four\u2010week voluntary wheel running counteracted muscle weakness in PyMT mice which was accompanied by reduced intrinsic stress and improved mitochondrial and antioxidant profiles and activities that aligned with muscles of healthy mice.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12944","type":"journal-article","created":{"date-parts":[[2022,2,16]],"date-time":"2022-02-16T03:34:09Z","timestamp":1644982449000},"page":"1151-1163","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Exercise reduces intramuscular stress and counteracts muscle weakness in mice with breast cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Theresa","family":"Mader","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology Karolinska Institutet, Biomedicum  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Chaillou","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology Karolinska Institutet, Biomedicum  Stockholm Sweden"},{"name":"School of Health Sciences \u00d6rebro University  \u00d6rebro Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estela Santos","family":"Alves","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology Karolinska Institutet, Biomedicum  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baptiste","family":"Jude","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology Karolinska Institutet, Biomedicum  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur J.","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology Karolinska Institutet, Biomedicum  Stockholm Sweden"},{"name":"Muscle Health Research Centre, School of Kinesiology and Health Science, Faculty of Health Toronto York University  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellinor","family":"Kenne","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology Karolinska Institutet, Biomedicum  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Mijwel","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology Karolinska Institutet, Biomedicum  Stockholm Sweden"},{"name":"Department of Neurobiology, Care Sciences and Society Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Kurzejamska","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara Theresa","family":"Vincent","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology Uppsala University  Uppsala Sweden"},{"name":"Department of Microbiology NYU Grossman School of Medicine  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helene","family":"Rundqvist","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Clinical Physiology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1222-9473","authenticated-orcid":false,"given":"Johanna T.","family":"Lanner","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Molecular Muscle Physiology and Pathophysiology Karolinska Institutet, Biomedicum  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,2,15]]},"reference":[{"key":"e_1_2_8_2_1","first-page":"172","article-title":"Cure in metastatic breast cancer","volume":"11","author":"Westphal T","year":"2018","journal-title":"Memory"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12565"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.105"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdt551"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12165"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-8049(00)00144-1"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3109\/0284186X.2014.998275"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-010-9536-x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2016.07.010"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-07-0771"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201700968R"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63568-7"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202100066R"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.11.029"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.13261"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2017.056"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a003996"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1969.tb00674.x"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1995.sp020883"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.49920"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13694-1"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41523-020-0162-2"},{"key":"e_1_2_8_24_1","first-page":"84","article-title":"The relationship between skeletal muscle mitochondrial citrate synthase activity and whole body oxygen uptake adaptations in response to exercise training","volume":"6","author":"Vigels\u00f8 A","year":"2014","journal-title":"Int J Physiol Pathophysiol Pharmacol"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00584"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00871.2012"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03148-8"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00898.2007"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270650"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvn327"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201812152"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.12619"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00031.2010"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202100263R"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.34613"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.59996"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz766"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-020-07217-1"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-01560-0"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11344"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0080123"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.293.20.2479"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-146308"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12899"}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.12944","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcsm.12944","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.12944","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T16:32:16Z","timestamp":1692981136000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.12944"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,15]]},"references-count":43,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["10.1002\/jcsm.12944"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.12944","archive":["Portico"],"relation":{},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,15]]},"assertion":[{"value":"2021-06-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-01-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}