{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:53:24Z","timestamp":1790049204430,"version":"4.0.1"},"reference-count":75,"publisher":"Wiley","license":[{"start":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T00:00:00Z","timestamp":1762041600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"abstract":"\n Abstract<\/jats:title>\n \n The degree to which mitochondrial\u2010linked programmed cell death pathways contribute to skeletal muscle atrophy during cancer remains unknown. Here we combined a novel and robust mouse model of metastatic ovarian cancer with chronic administration of the mitochondrial\u2010targeted antioxidant SkQ1 to determine the time\u2010dependent and muscle\u2010specific relationships of mitochondrial\u2010linked apoptotic and necroptotic signalling to the development of muscle atrophy in the type IIB\u2010rich gastrocnemius. Early\u2010stage ovarian cancer reduced type IIB fibre cross\u2010sectional area in the gastrocnemius but did not alter mitochondrial H\n 2<\/jats:sub>\n O\n 2<\/jats:sub>\n emission despite increased activities of mitochondrial\u2010linked caspase\u20109 and \u20103 regulators of apoptosis. During late\u2010stage ovarian cancer sustained atrophy was associated with increased mitochondrial H\n 2<\/jats:sub>\n O\n 2<\/jats:sub>\n emission potential\n in vitro<\/jats:italic>\n , a greater probability of calcium\u2010triggered mitochondrial permeability transition and increases in downstream caspase\u20109 and \u20103 activities. SkQ1 attenuated mitochondrial H\n 2<\/jats:sub>\n O\n 2<\/jats:sub>\n emission and caspase\u20109 and \u20103 activities in late\u2010stage ovarian cancer but did not prevent atrophy. Necroptosis markers were heterogeneous across time with total RIPK1 increasing during early\u2010stage cancer, which reverted to normal levels by late stages, whereas phosphorylated RIPK3 decreased below control levels. These discoveries indicate that preventing increases in mitochondrial\u2010linked apoptotic caspase\u20109 and \u20103 activities during late\u2010stage ovarian cancer with SkQ1 does not prevent atrophy of type II B fibres. Furthermore necroptotic markers are inconclusive during cancer in this muscle type but are not modified by SkQ1. These results do not support a causal relationship between mitochondrial H\n 2<\/jats:sub>\n O\n 2<\/jats:sub>\n \u2010linked apoptotic or necroptotic signalling and atrophy in type IIB fibres during ovarian cancer but do not rule out potential relationships in other muscle types.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Cancer increases mitochondrial reactive oxygen species (ROS) in skeletal muscle during atrophy, but the role of ROS in regulating cell death remains unknown.<\/jats:p>\n <\/jats:list-item>\n \n We show that attenuating gastrocnemius mitochondrial ROS with the mitochondrial\u2010targeted antioxidant SkQ1 prevented mitochondrial\u2010linked pro\u2010apoptotic caspase 9\u2010 and \u20103 activities but did not affect markers of necroptosis in a mouse model of ovarian cancer.<\/jats:p>\n <\/jats:list-item>\n \n Reductions in gastrocnemius muscle fibre cross\u2010sectional areas and the wet weights of several muscles were not prevented by SkQ1.<\/jats:p>\n <\/jats:list-item>\n \n These findings demonstrate that mitochondrial ROS regulate apoptotic caspases but not necroptotic proteins, and neither pathway is linked to gastrocnemius atrophy in mice with ovarian cancer.<\/jats:p>\n <\/jats:list-item>\n \n The degree to which mitochondrial ROS\u2010linked cell death pathways regulate muscle mass in other muscle types and cancer models requires further investigation.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp287912","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T04:54:37Z","timestamp":1762145677000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The mitochondrial\u2010targeted antioxidant SkQ1 prevents skeletal muscle mitochondrial\u2010apoptotic but not necroptotic signalling during ovarian cancer"],"prefix":"10.1113","author":[{"given":"Shahrzad","family":"Khajehzadehshoushtar","sequence":"first","affiliation":[{"name":"School of Kinesiology & Health Science, Muscle Health Research Centre York University Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca J.","family":"Delfinis","sequence":"additional","affiliation":[{"name":"School of Kinesiology & Health Science, Muscle Health Research Centre York University Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4588-5378","authenticated-orcid":false,"given":"Fasih A.","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Kinesiology and Health Sciences University of Waterloo Waterloo Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison C.","family":"Garibotti","sequence":"additional","affiliation":[{"name":"School of Kinesiology & Health Science, Muscle Health Research Centre York University Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivam","family":"Gandhi","sequence":"additional","affiliation":[{"name":"School of Kinesiology & Health Science, Muscle Health Research Centre York University Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0799-014X","authenticated-orcid":false,"given":"Aditya N.","family":"Brahmbhatt","sequence":"additional","affiliation":[{"name":"School of Kinesiology & Health Science, Muscle Health Research Centre York University Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke A.","family":"Morris","sequence":"additional","affiliation":[{"name":"School of Kinesiology & Health Science, Muscle Health Research Centre York University Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Garlisi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Guelph Guelph Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Lauks","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Guelph Guelph Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Aitken","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Guelph Guelph Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0596-6061","authenticated-orcid":false,"given":"Leslie","family":"Ogilvie","sequence":"additional","affiliation":[{"name":"Department of Human Health and Nutritional Sciences University of Guelph Guelph Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhu\u2010Xu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Western University London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4482-547X","authenticated-orcid":false,"given":"Jeremy A.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Human Health and Nutritional Sciences University of Guelph Guelph Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9304-3557","authenticated-orcid":false,"given":"Joe","family":"Quadrilatero","sequence":"additional","affiliation":[{"name":"Department of Kinesiology and Health Sciences University of Waterloo Waterloo Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Petrik","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Guelph Guelph Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5745-5888","authenticated-orcid":false,"given":"Christopher G. 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