{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:43:00Z","timestamp":1792600980631,"version":"4.5.0"},"reference-count":20,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Incretin\u2010based therapies such as glucagon\u2010like peptide\u20101 receptor agonists (GLP\u20101Ras), dual GLP\u20101\/GIP agonists and amylin analogues have demonstrated significant weight loss benefits. However, their impact on skeletal muscle mitochondrial function, particularly under metabolic stress, remains unclear. This study aimed to investigate the effects of semaglutide (GLP\u20101RA), tirzepatide (dual GLP\u20101\/GIP agonist) and cagrilintide (amylin analogue) on mitochondrial function in C2C12 skeletal muscle myotubes under both healthy and lipotoxic (palmitic acid\u2010treated) conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Differentiated C2C12 myotubes were treated with doses of each drug for 48\u2009h and 5 days. Mitochondrial respiration was assessed using the Seahorse XFp analyser, mitochondrial DNA (mtDNA) copy number and oxidative phosphorylation (OXPHOS) complex protein expression were measured by qPCR and western blotting. Key findings were repeated in primary human skeletal muscle cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Palmitic acid (PA) significantly impaired mitochondrial function, reducing basal oxygen consumption rate (OCR) by 22% (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0056) and ATP production by 25% (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0022). In healthy myotubes, semaglutide and cagrilintide transiently reduced basal respiration (\u219321%\u201328%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and ATP production (\u219324%\u201331%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) at 48\u2009h, along with reductions in Complexes I, III and IV protein expression, all of which resolved by 5\u2009days. Tirzepatide significantly increased maximal respiration (\u219120%\u201325%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.005) and spare respiratory capacity (\u219122%\u201330%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.005) after 5\u2009days. In PA\u2010treated myotubes, semaglutide and cagrilintide acutely worsened mitochondrial impairment (\u2193ATP production by ~20%\u201325%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), but these effects resolved by Day 5. Tirzepatide initially suppressed mitochondrial function (\u2193ATP production,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0087) but reversed these effects by Day 5, significantly improving ATP production (\u219127%\u201330%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.005), basal respiration (\u219120%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0152), and coupling efficiency. mtDNA content remained unchanged across all conditions. Similar responses were noted in human myotubes, with a transient reduction in respiration for semaglutide and cagrilintide (\u219330%\u201362%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) at 48\u2009h and a significant improvement in maximal respiration for tirzepatide at 5\u2009days (\u219142%\u201352%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0022).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Incretin\u2010based therapies exert distinct, time and dose\u2010dependent effects on skeletal muscle mitochondrial function. Tirzepatide promoted sustained improvements in mitochondrial respiration under both healthy and lipotoxic conditions, indicating potential benefits for maintaining skeletal muscle bioenergetic function. These findings underscore the need for further mechanistic studies and suggest that tirzepatide may have the potential to support skeletal muscle health in metabolic disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70254","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T07:48:11Z","timestamp":1773906491000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mitochondrial Adaptations in Skeletal Muscle Following Incretin\u2010Based Therapies: In\u00a0Vitro"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7660-7746","authenticated-orcid":false,"given":"Victoria","family":"Old","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Sciences, College of Life Sciences University of Leicester  Leicester UK"},{"name":"NIHR Leicester Biomedical Research Centre University of Leicester  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Davies","sequence":"additional","affiliation":[{"name":"NIHR Leicester Biomedical Research Centre University of Leicester  Leicester UK"},{"name":"Diabetes Research Centre University of Leicester  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Denniff","sequence":"additional","affiliation":[{"name":"Division of Respiratory Sciences, College of Life Sciences University of Leicester  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratik","family":"Choudhary","sequence":"additional","affiliation":[{"name":"NIHR Leicester Biomedical Research Centre University of Leicester  Leicester UK"},{"name":"Diabetes Research Centre University of Leicester  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Eastley","sequence":"additional","affiliation":[{"name":"Leicester Orthopaedics University Hospitals of Leicester  Leicester UK"},{"name":"Division of Cancer Studies University of Leicester  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert\u00a0U.","family":"Ashford","sequence":"additional","affiliation":[{"name":"Leicester Orthopaedics University Hospitals of Leicester  Leicester UK"},{"name":"Division of Cancer Studies University of Leicester  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Watson","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Sciences, College of Life Sciences University of Leicester  Leicester UK"},{"name":"NIHR Leicester Biomedical Research Centre University of Leicester  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)02750-2"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2032183"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00213-0"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2206038"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01200-X"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)01751-7"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2502081"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2502082"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.3803\/EnM.2019.34.3.247"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0b013e32833c3026"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2016.12.005"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13677"},{"key":"e_1_2_7_14_1","doi-asserted-by":"crossref","unstructured":"L. A.Baker T. F.O'Sullivan K. A.Robinson et\u00a0al. \u201cEstablishment and Characterisation of Primary Skeletal Muscle Cell Cultures From Patients With Advanced Chronic Kidney Disease \u201d bioRxiv (2020) 2020.11.16.384263.","DOI":"10.1101\/2020.11.16.384263"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26020788"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.133429"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.14843"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00845-X"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2022.119300"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01931-z"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2024.1431292"}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.70254","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcsm.70254","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.70254","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T09:32:20Z","timestamp":1788341540000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.70254"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,19]]},"references-count":20,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/jcsm.70254"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.70254","archive":["Portico"],"relation":{},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,19]]},"assertion":[{"value":"2025-07-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70254"}}