{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:11:15Z","timestamp":1790392275017,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T00:00:00Z","timestamp":1594857600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","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":[[2020,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Surgery can lead to significant muscle loss, which increases recovery time and associates with increased mortality. Muscle loss is not uniform, with some patients losing significant muscle mass and others losing relatively little, and is likely to be accompanied by marked changes in circulating metabolites and proteins. Determining these changes may help understand the variability and identify novel therapeutic approaches or markers of muscle wasting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To determine the association between muscle loss and circulating metabolites, we studied 20 male patients (median age, 70.5, interquartile range, 62.5\u201375) undergoing aortic surgery. Muscle mass was determined before and 7\u00a0days after surgery and blood samples were taken before surgery, and 1, 3, and 7\u00a0days after surgery. The circulating metabolome and proteome were determined using commercial services (Metabolon and SomaLogic).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Ten patients lost more than 10% of the cross\u2010sectional area of the rectus femoris (RF<jats:sub>CSA<\/jats:sub>) and were defined as wasting. Metabolomic analysis showed that 557 circulating metabolites were altered following surgery (<jats:italic>q<\/jats:italic>\u00a0&lt;\u00a00.05) in the whole cohort and 104 differed between wasting and non\u2010wasting patients (<jats:italic>q<\/jats:italic>\u00a0&lt;\u00a00.05). Weighted genome co\u2010expression network analysis, identified clusters of metabolites, both before and after surgery, that associated with muscle mass and function (<jats:italic>r<\/jats:italic>\u00a0=\u00a0\u22120.72, <jats:italic>p<\/jats:italic>\u00a0=\u00a06\u00a0\u00d7\u00a010<jats:sup>\u22124<\/jats:sup> with RF<jats:sub>CSA<\/jats:sub> on Day 0, <jats:italic>P<\/jats:italic>\u00a0=\u00a03\u00a0\u00d7\u00a010<jats:sup>\u22124<\/jats:sup> with RF<jats:sub>CSA<\/jats:sub> on Day 7 and <jats:italic>r<\/jats:italic>\u00a0=\u00a0\u22120.73, <jats:italic>P<\/jats:italic>\u00a0=\u00a05\u00a0\u00d7\u00a010<jats:sup>\u22124<\/jats:sup> with hand\u2010grip strength on Day 7). These clusters were mainly composed of acyl carnitines and dicarboxylates indicating that pre\u2010existing mitochondrial dysfunction contributes to muscle loss following surgery. Surgery elevated cortisol to the same extent in wasting and non\u2010wasting patients, but the cortisol:cortisone ratio was higher in the wasting patients (Day 3 <jats:italic>P<\/jats:italic>\u00a0=\u00a00.043 and Day 7 <jats:italic>P<\/jats:italic>\u00a0=\u00a00.016). Wasting patients also showed a greater increase in circulating nucleotides 3\u00a0days after surgery. Comparison of the metabolome with inflammatory markers identified by SOMAscan\u00ae showed that pre\u2010surgical mitochondrial dysfunction was associated with growth differentiation factor 15 (GDF\u201015) (<jats:italic>r<\/jats:italic>\u00a0=\u00a00.79, <jats:italic>P<\/jats:italic>\u00a0=\u00a02\u00a0\u00d7\u00a010<jats:sup>\u22124<\/jats:sup>) and that GDF\u201015, interleukin (IL)\u20108), C\u2010C motif chemokine 23 (CCL\u201023), and IL\u201015 receptor subunit alpha (IL\u201015RA) contributed to metabolic changes in response to surgery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We show that pre\u2010existing mitochondrial dysfunction and reduced cortisol inactivation contribute to muscle loss following surgery. The data also implicate GDF\u201015 and IL\u201015RA in mitochondrial dysfunction.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12597","type":"journal-article","created":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T06:05:41Z","timestamp":1594965941000},"page":"1321-1335","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Metabolic profiling shows pre\u2010existing mitochondrial dysfunction contributes to muscle loss in a model of ICU\u2010acquired weakness"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8975-7293","authenticated-orcid":false,"given":"Paul R.","family":"Kemp","sequence":"first","affiliation":[{"name":"Cardiovascular and Respiratory Interface Section, National Heart and Lung Institute Imperial College London, South Kensington Campus  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Paul","sequence":"additional","affiliation":[{"name":"Cardiovascular and Respiratory Interface Section, National Heart and Lung Institute Imperial College London, South Kensington Campus  London UK"},{"name":"Department of Intensive Care Guy's and St. Thomas' NHS Foundation Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron C.","family":"Hinken","sequence":"additional","affiliation":[{"name":"Muscle Metabolism Discovery Performance Unit GlaxoSmithKline, Inc  Collegeville PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Neil","sequence":"additional","affiliation":[{"name":"Muscle Metabolism Discovery Performance Unit GlaxoSmithKline, Inc  Collegeville PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Russell","sequence":"additional","affiliation":[{"name":"Muscle Metabolism Discovery Performance Unit GlaxoSmithKline, Inc  Collegeville PA USA"},{"name":"Edgewise Therapeutics  Boulder CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Griffiths","sequence":"additional","affiliation":[{"name":"Cardiovascular and Respiratory Interface Section, National Heart and Lung Institute Imperial College London, South Kensington Campus  London 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