{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T22:58:14Z","timestamp":1791845894790,"version":"4.3.4"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cancer cachexia is a multifactorial metabolic syndrome marked by progressive skeletal muscle loss, reduced function, and increased mortality. Mitochondrial dysfunction is a key driver of this phenotype. MOTS-c, a mitochondrial-derived peptide that regulates metabolic homeostasis and mimics exercise signaling, may counteract cachexia, but its role remains largely unexplored, and human studies using MOTS-c in subjects with cancer cachexia are needed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Differentiated myotubes were treated with MOTS-c (50 \u03bcM) to assess intracellular signaling.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , male mice were inoculated with Colon-26 (C26) carcinoma cells and treated daily with MOTS-c (15 mg\/kg\/2x Day, i.p.) or vehicle. Body weight was monitored daily. At euthanasia, organ and skeletal muscle masses were measured. Molecular analyses focused on FOXO signaling, atrogene expression (MuRF1, Atrogin-1), and mitochondrial biogenesis markers, including PGC-1\u03b1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>In vitro<\/jats:italic>\n                      , MOTS-c increased PGC-1\u03b1 mRNA (+84.6%) and AMPK phosphorylation (+103.1%). C26 tumor-bearing mice exhibited significant systemic wasting (~9% body weight loss). Although MOTS-c did not prevent total body weight or fat loss, it significantly preserved skeletal muscle mass, rescuing quadriceps weight (+12% vs. C26 vehicle;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.05) and trending toward protection of gastrocnemius mass and EDL function. Cachexia-induced upregulation of Atrogin-1 (+8.6-fold) and MuRF1 (+16-fold) was attenuated by MOTS-c, accompanied by increased inhibitory pFOXO1 (+80%), reduced pFOXO3a (\u221239%), and partial restoration of PGC-1\u03b1 protein (+143%).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings demonstrate that MOTS-c partially protects against skeletal muscle loss in C26 cachexia by modulating FOXO-driven catabolic signaling and promoting mitochondrial biogenesis, supporting its therapeutic potential in cancer cachexia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1838178","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T04:36:18Z","timestamp":1779683778000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia"],"prefix":"10.3389","volume":"13","author":[{"given":"Nicholas A.","family":"Jamnick","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick D.","family":"Livingston","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb J.","family":"Gammon","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia M.","family":"Weinzierl","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah J.","family":"Novinger","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Colorado Anschutz","place":["Aurora, CO, United States"]},{"name":"Cancer Center, University of Colorado Anschutz","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Bonetto","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Colorado Anschutz","place":["Aurora, CO, United States"]},{"name":"Cancer Center, University of Colorado Anschutz","place":["Aurora, CO, United States"]},{"name":"Colorado Nutrition Obesity Research Center, University of Colorado Anschutz","place":["Aurora, CO, United 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