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Although it directly causes 20% of all cancer\u2010related deaths, there are currently no model systems that encompass the entire multifaceted syndrome, nor are there any effective therapeutic treatments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A novel model of systemic metastasis was evaluated for the comprehensive CACS (metastasis, skeletal muscle and adipose tissue wasting, inflammation, anorexia, anemia, elevated protein breakdown, hypoalbuminemia, and metabolic derangement) in both males and females.\n                      <jats:italic>Ex vivo<\/jats:italic>\n                      skeletal muscle analysis was utilized to determine ubiquitin proteasome degradation pathway activation. A novel ketone diester (\n                      <jats:italic>R\/S<\/jats:italic>\n                      1,3\u2010Butanediol Acetoacetate Diester) was assessed in multifaceted catabolic environments to determine anti\u2010atrophy efficacy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Here, we show that the VM\u2010M3 mouse model of systemic metastasis demonstrates a novel, immunocompetent, logistically feasible, repeatable phenotype with progressive tumor growth, spontaneous metastatic spread, and the full multifaceted CACS with sex dimorphisms across tissue wasting. We also demonstrate that the ubiquitin proteasome degradation pathway was significantly upregulated in association with reduced insulin\u2010like growth factor\u20101\/insulin and increased FOXO3a activation, but not tumor necrosis factor\u2010\u03b1\u2010induced nuclear factor\u2010kappa B activation, driving skeletal muscle atrophy. Additionally, we show that\n                      <jats:italic>R\/S<\/jats:italic>\n                      1,3\u2010Butanediol Acetoacetate Diester administration shifted systemic metabolism, attenuated tumor burden indices, reduced atrophy\/catabolism and mitigated comorbid symptoms in both CACS and cancer\u2010independent atrophy environments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest the ketone diester attenuates multifactorial CACS skeletal muscle atrophy and inflammation\u2010induced catabolism, demonstrating anti\u2010catabolic effects of ketone bodies in multifactorial atrophy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.12554","type":"journal-article","created":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T03:25:52Z","timestamp":1585797952000},"page":"973-996","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Ketone Bodies Attenuate Wasting in Models of Atrophy"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5491-3919","authenticated-orcid":false,"given":"Andrew P.","family":"Koutnik","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology Morsani College of Medicine, University of South Florida  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela M.","family":"Poff","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology Morsani College of Medicine, University of South Florida  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan P.","family":"Ward","sequence":"additional","affiliation":[{"name":"Department of Cancer Physiology Moffitt Cancer Center, H. Lee Moffitt Cancer Center and Research Institute  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine M.","family":"DeBlasi","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology Morsani College of Medicine, University of South Florida  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maricel A.","family":"Soliven","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology Morsani College of Medicine, University of South Florida  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Romero","sequence":"additional","affiliation":[{"name":"School of Kinesiology Auburn University  Auburn AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Roberson","sequence":"additional","affiliation":[{"name":"School of Kinesiology Auburn University  Auburn AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl D.","family":"Fox","sequence":"additional","affiliation":[{"name":"School of Kinesiology Auburn University  Auburn AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Roberts","sequence":"additional","affiliation":[{"name":"School of Kinesiology Auburn University  Auburn AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic P.","family":"D'Agostino","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology Morsani College of Medicine, University of South Florida  Tampa FL USA"},{"name":"Institute for Human and Machine Cognition  Ocala FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,2]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70218-7"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clnu.2008.06.013"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3829"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000441-193211000-00002"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12167"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2015.09.002"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12475"},{"key":"e_1_2_8_9_1","first-page":"257","article-title":"What is cancer anorexia\u2010cachexia syndrome? 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