{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:15:27Z","timestamp":1788455727259,"version":"build-2803163510"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T00:00:00Z","timestamp":1780704000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T00:00:00Z","timestamp":1780704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Appl Physiol"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Chronic myeloid leukemia (CML) patients receiving tyrosine kinase inhibitors (TKIs) often report muscle complaints (MC). Strategies to prevent or attenuate these muscle complaints remain enigmatic as the underlying mechanism is unclear, although a central role for mitochondria is proposed. We investigated the effects of TKIs on cellular metabolism in muscle biopsies of CML patients (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200920), compared with healthy controls (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200910) and whether these changes may be linked to muscle complaints. C2C12 myotubes were used to further explore the effects of TKIs on muscle metabolism\n                    <jats:italic>in vitro.<\/jats:italic>\n                    We found that TKI muscle concentrations in CML patients aligned with the concentrations at which cytotoxicity could be observed in C2C12 myotubes, and that muscle to plasma ratios tended to correlate with the degree of MC in CML patients. In C2C12 myotubes, acute TKI incubation of C2C12 myotubes resulted in alterations in energy metabolism, showing a shift from glycolysis to oxidative phosphorylation. CML patients without MC showed higher oxidative capacity, characterized by higher mitochondrial complex activities in skeletal muscle and occurrence of the first ventilatory threshold at a higher percentage of peak oxygen uptake during maximal exercise compared to patients with MC. Taken together, these observations raise the possibility that TKIs may affect cellular energy metabolism and may contribute to muscle complaints.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>Trial registration<\/jats:italic>\n                    The Netherlands Trial Registry identifier NTR6373.\n                  <\/jats:p>","DOI":"10.1007\/s00421-026-06287-6","type":"journal-article","created":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T12:17:26Z","timestamp":1780748246000},"page":"5017-5025","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of tyrosine kinase inhibitors on skeletal muscle metabolism: a link with muscle complaints"],"prefix":"10.1007","volume":"126","clinical-trial-number":[{"clinical-trial-number":"ntr6373","registry":"10.18810\/dutch-trial-register"}],"author":[{"given":"Lando","family":"Janssen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte A.","family":"Hoogstraten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeltje A. E.","family":"Allard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom J. J.","family":"Schirris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria T. E.","family":"Hopman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole M. A.","family":"Blijlevens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2852-5274","authenticated-orcid":false,"given":"Silvie","family":"Timmers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,6]]},"reference":[{"issue":"3","key":"6287_CR25","doi-asserted-by":"publisher","first-page":"C615","DOI":"10.1152\/ajpcell.00540.2019","volume":"318","author":"AM Abdelmoez","year":"2020","unstructured":"Abdelmoez AM et al (2020) Comparative profiling of skeletal muscle models reveals heterogeneity of transcriptome and metabolism. Am J Physiology-Cell Physiol 318(3):C615\u2013C626","journal-title":"Am J Physiology-Cell Physiol"},{"issue":"6","key":"6287_CR12","doi-asserted-by":"publisher","first-page":"2020","DOI":"10.1152\/jappl.1986.60.6.2020","volume":"60","author":"WL Beaver","year":"1986","unstructured":"Beaver WL, Wasserman K, Whipp BJ (1986) A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol (1985) 60(6):2020\u20132027","journal-title":"J Appl Physiol (1985)"},{"issue":"10","key":"6287_CR15","doi-asserted-by":"publisher","first-page":"R100","DOI":"10.1186\/gb-2006-7-10-r100","volume":"7","author":"AE Carpenter","year":"2006","unstructured":"Carpenter AE et al (2006) CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol 7(10):R100","journal-title":"Genome Biol"},{"key":"6287_CR26","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.bcp.2018.07.001","volume":"155","author":"VL Damaraju","year":"2018","unstructured":"Damaraju VL et al (2018) Multitargeted kinase inhibitors imatinib, sorafenib and sunitinib perturb energy metabolism and cause cytotoxicity to cultured C2C12 skeletal muscle derived myotubes. Biochem Pharmacol 155:162\u2013171","journal-title":"Biochem Pharmacol"},{"issue":"7","key":"6287_CR5","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1038\/leu.2013.51","volume":"27","author":"F Efficace","year":"2013","unstructured":"Efficace F et al (2013) Chronic fatigue is the most important factor limiting health-related quality of life of chronic myeloid leukemia patients treated with imatinib. Leukemia 27(7):1511\u20131519","journal-title":"Leukemia"},{"issue":"19","key":"6287_CR19","doi-asserted-by":"publisher","first-page":"6661","DOI":"10.1158\/1078-0432.CCR-04-0039","volume":"10","author":"S Gottschalk","year":"2004","unstructured":"Gottschalk S et al (2004) Imatinib (STI571)-mediated changes in glucose metabolism in human leukemia BCR-ABL-positive cells. Clin Cancer Res 10(19):6661\u20136668","journal-title":"Clin Cancer Res"},{"issue":"6","key":"6287_CR1","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1038\/leu.2009.38","volume":"23","author":"A Hochhaus","year":"2009","unstructured":"Hochhaus A et al (2009) Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 23(6):1054\u20131061","journal-title":"Leukemia"},{"issue":"12","key":"6287_CR2","doi-asserted-by":"publisher","first-page":"3123","DOI":"10.1002\/cncr.26679","volume":"118","author":"X Huang","year":"2012","unstructured":"Huang X, Cortes J, Kantarjian H (2012) Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Cancer 118(12):3123\u20133127","journal-title":"Cancer"},{"issue":"2","key":"6287_CR3","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/leu.2010.215","volume":"25","author":"E Jabbour","year":"2011","unstructured":"Jabbour E, Deininger M, Hochhaus A (2011) Management of adverse events associated with tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia 25(2):201\u2013210","journal-title":"Leukemia"},{"issue":"4","key":"6287_CR8","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1373\/clinchem.2006.078873","volume":"53","author":"AJ Janssen","year":"2007","unstructured":"Janssen AJ et al (2007) Spectrophotometric assay for complex I of the respiratory chain in tissue samples and cultured fibroblasts. Clin Chem 53(4):729\u2013734","journal-title":"Clin Chem"},{"issue":"8","key":"6287_CR7","doi-asserted-by":"publisher","first-page":"2116","DOI":"10.1038\/s41375-019-0443-7","volume":"33","author":"L Janssen","year":"2019","unstructured":"Janssen L et al (2019) Skeletal muscle toxicity associated with tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia. Leukemia 33(8):2116\u20132120","journal-title":"Leukemia"},{"key":"6287_CR6","unstructured":"Janssen L et al (2020) Fatigue in chronic myeloid leukemia patients on tyrosine kinase inhibitor therapy: predictors and the relationship with physical activity. Haematologica"},{"issue":"2","key":"6287_CR17","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1152\/physrev.00002.2019","volume":"100","author":"L Janssen","year":"2020","unstructured":"Janssen L et al (2020) Muscle Toxicity of Drugs: When Drugs Turn Physiology into Pathophysiology. Physiol Rev 100(2):633\u2013672","journal-title":"Physiol Rev"},{"issue":"10","key":"6287_CR20","doi-asserted-by":"publisher","first-page":"3442","DOI":"10.1158\/1078-0432.CCR-08-3291","volume":"15","author":"DJ Kominsky","year":"2009","unstructured":"Kominsky DJ et al (2009) Abnormalities in glucose uptake and metabolism in imatinib-resistant human BCR-ABL-positive cells. Clin Cancer Res 15(10):3442\u20133450","journal-title":"Clin Cancer Res"},{"issue":"10","key":"6287_CR10","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.1111\/bcp.13327","volume":"83","author":"NAG Lankheet","year":"2017","unstructured":"Lankheet NAG et al (2017) Optimizing the dose in cancer patients treated with imatinib, sunitinib and pazopanib. Br J Clin Pharmacol 83(10):2195\u20132204","journal-title":"Br J Clin Pharmacol"},{"issue":"11","key":"6287_CR23","doi-asserted-by":"publisher","first-page":"4765","DOI":"10.1007\/s00277-024-05924-4","volume":"103","author":"C Lau","year":"2024","unstructured":"Lau C et al (2024) Varying concentrations of tyrosine kinase inhibitors in chronic myeloid leukemia patients following bariatric surgery: a case series. Ann Hematol 103(11):4765\u20134771","journal-title":"Ann Hematol"},{"issue":"14","key":"6287_CR4","doi-asserted-by":"publisher","first-page":"2381","DOI":"10.1200\/JCO.2009.26.3087","volume":"28","author":"D Marin","year":"2010","unstructured":"Marin D et al (2010) Adherence Is the Critical Factor for Achieving Molecular Responses in Patients With Chronic Myeloid Leukemia Who Achieve Complete Cytogenetic Responses on Imatinib. J Clin Oncol 28(14):2381\u20132388","journal-title":"J Clin Oncol"},{"key":"6287_CR16","doi-asserted-by":"crossref","unstructured":"Nicholls DG et al (2010) Bioenergetic profile experiment using C2C12 myoblast cells. J visualized experiments: JoVE, (46): p. 2511","DOI":"10.3791\/2511-v"},{"issue":"1","key":"6287_CR13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.32604\/biocell.2013.37.001","volume":"37","author":"L Pronsato","year":"2013","unstructured":"Pronsato L et al (2013) High passage numbers induce resistance to apoptosis in C2C12 muscle cells. Biocell 37(1):1\u20139","journal-title":"Biocell"},{"issue":"6","key":"6287_CR22","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1182\/blood.2022018196","volume":"142","author":"S Qiu","year":"2023","unstructured":"Qiu S et al (2023) Metabolic adaptation to tyrosine kinase inhibition in leukemia stem cells. Blood 142(6):574\u2013588","journal-title":"Blood"},{"issue":"2","key":"6287_CR24","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1139\/o90-076","volume":"68","author":"V Sarabia","year":"1990","unstructured":"Sarabia V, Ramlal T, Klip A (1990) Glucose uptake in human and animal muscle cells in culture. Biochem Cell Biol 68(2):536\u2013542","journal-title":"Biochem Cell Biol"},{"issue":"3","key":"6287_CR14","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.cmet.2015.08.002","volume":"22","author":"TJ Schirris","year":"2015","unstructured":"Schirris TJ et al (2015) Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition. Cell Metab 22(3):399\u2013407","journal-title":"Cell Metab"},{"issue":"5930","key":"6287_CR18","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1126\/science.1160809","volume":"324","author":"MG Vander Heiden","year":"2009","unstructured":"Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Sci (New York N Y) 324(5930):1029\u20131033","journal-title":"Sci (New York N Y)"},{"key":"6287_CR9","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.jchromb.2013.08.013","volume":"937","author":"NP van Erp","year":"2013","unstructured":"van Erp NP et al (2013) A validated assay for the simultaneous quantification of six tyrosine kinase inhibitors and two active metabolites in human serum using liquid chromatography coupled with tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 937:33\u201343","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"issue":"4","key":"6287_CR21","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1158\/1078-0432.CCR-17-2697","volume":"24","author":"GA Vitiello","year":"2018","unstructured":"Vitiello GA et al (2018) Mitochondrial Inhibition Augments the Efficacy of Imatinib by Resetting the Metabolic Phenotype of Gastrointestinal Stromal Tumor. Clin Cancer Res 24(4):972\u2013984","journal-title":"Clin Cancer Res"},{"issue":"5","key":"6287_CR11","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1097\/FTD.0b013e3181b2c8cf","volume":"31","author":"Y Wang","year":"2009","unstructured":"Wang Y et al (2009) A therapeutic drug monitoring algorithm for refining the imatinib trough level obtained at different sampling times. Ther Drug Monit 31(5):579\u2013584","journal-title":"Ther Drug Monit"},{"issue":"1","key":"6287_CR27","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1093\/toxsci\/kfn157","volume":"106","author":"Y Will","year":"2008","unstructured":"Will Y et al (2008) Effect of the Multitargeted Tyrosine Kinase Inhibitors Imatinib, Dasatinib, Sunitinib, and Sorafenib on Mitochondrial Function in Isolated Rat Heart Mitochondria and H9c2 Cells. Toxicol Sci 106(1):153\u2013161","journal-title":"Toxicol Sci"}],"container-title":["European Journal of Applied Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00421-026-06287-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00421-026-06287-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00421-026-06287-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T16:18:03Z","timestamp":1788452283000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00421-026-06287-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,6]]},"references-count":27,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["6287"],"URL":"https:\/\/doi.org\/10.1007\/s00421-026-06287-6","relation":{},"ISSN":["1439-6319","1439-6327"],"issn-type":[{"value":"1439-6319","type":"print"},{"value":"1439-6327","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,6]]},"assertion":[{"value":"15 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"No author has conflict of interest related to this work.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}]}}