{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T02:29:05Z","timestamp":1791253745518,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2013,1,24]],"date-time":"2013-01-24T00:00:00Z","timestamp":1358985600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2013,6]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. Inhibiting the signaling of the transcription factor nuclear factor kappa B (NF\u2010\u03baB) largely prevents cancer\u2010induced muscle wasting in murine models. We have previously shown the utility of Compound A, a highly selective novel NF\u2010\u03baB inhibitor that targets the I\u03baB kinase complex, to provide clinical benefit in cancer\u2010induced skeletal muscle and cardiac atrophy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using a metabolomics approach, we describe the changes found between cachectic and noncachectic gastrocnemius muscles before and after Compound A treatment at various doses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of the 234 metabolites in the gastrocnemius, cachexia\u2010induced changes in gastrocnemius metabolism reset the steady\u2010state abundances of 42 metabolites (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). These changes, not evenly distributed across biochemical categories, are concentrated in amino acids, peptides, carbohydrates and energetics intermediates, and lipids. The gastrocnemius glycolytic pathway is markedly altered\u2014changes consistent with tumor Warburg physiology. This is the first account of a Warburg effect that is not exclusively restricted to cancer cells or rapidly proliferating nonmalignant cells. Cachectic gastrocnemius also displays tricarboxylic acid cycle disruptions, signs of oxidative stress, and impaired redox homeostasis. Compound A only partially rescues the phenotype of the cachectic gastrocnemius, failing to restore the gastrocnemius\u2019 baseline metabolic profile.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The findings in the present manuscript enumerate the metabolic consequences of cachexia in the gastrocnemius and demonstrate that NF\u2010kB targeted treatment only partly rescues the cachectic metabolic phenotype. These data strengthen the previous findings from metabolomic characterization of serum in cachectic animals, suggesting that many of the metabolic alterations observed in the blood originate in the diseased muscle. These findings provide significant insight into the complex pathophysiology of cancer cachexia and provide objective criteria for evaluating future therapeutics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Electronic supplementary material<\/jats:title><jats:p>The online version of this article (doi:10.1007\/s13539\u2010012\u20100101\u20107) contains supplementary material, which is available to authorized users.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s13539-012-0101-7","type":"journal-article","created":{"date-parts":[[2013,1,23]],"date-time":"2013-01-23T07:25:55Z","timestamp":1358925955000},"page":"145-155","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Metabolic derangements in the gastrocnemius and the effect of Compound A therapy in a murine model of cancer cachexia"],"prefix":"10.1002","volume":"4","author":[{"given":"Hirak","family":"Der-Torossian","sequence":"first","affiliation":[{"name":"Division of Otolaryngology\u2013Head and Neck Surgery, Department of Surgery University of Vermont  Burlington VT"},{"name":"Vermont Cancer Center University of Vermont  Burlington VT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Wysong","sequence":"additional","affiliation":[{"name":"Department of Dermatology Stanford University  Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Shadfar","sequence":"additional","affiliation":[{"name":"Division of Otolaryngology\u2013Head and Neck Surgery, Department of Surgery University of North Carolina  Chapel Hill NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monte S.","family":"Willis","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine University of North Carolina  Chapel Hill NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"McDunn","sequence":"additional","affiliation":[{"name":"Metabolon Inc.  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