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Experimental research on the molecular mechanisms of long-term DOX treatment is modest, and its effect on both skeletal muscle and adipose tissue has not been studied in an integrative manner. Dexrazoxane (DEXRA) is used to prevent DOX-induced cancer-therapy-related cardiovascular dysfunction (CTRCD), but its impact on skeletal muscle and adipose tissue remains elusive. Therefore, this study aimed to investigate the long-term effects of DOX on adipose tissue and skeletal muscle metabolism, and evaluate whether DEXRA can mitigate these effects. To this end, 10-week-old male C57BL6\/J mice (n = 32) were divided into four groups: (1) DOX, (2) DOX-DEXRA combined, (3) DEXRA and (4) control. DOX (4 mg\/kg weekly) and DEXRA (40 mg\/kg weekly) were administered intraperitoneally over 6 weeks. Indirect calorimetry was used to assess metabolic parameters, followed by a molecular analysis and histological evaluation of skeletal muscle and adipose tissue. DOX treatment led to significant white adipose tissue (WAT) loss (74%) and moderate skeletal muscle loss (Gastrocnemius (GAS): 10%), along with decreased basal activity (53%) and energy expenditure (27%). A trend toward a reduced type IIa fiber cross-sectional area and a fast-to-slow fiber type switch in the Soleus muscle was observed. The WAT of DOX-treated mice displayed reduced Pparg (p &lt; 0.0001), Cd36 (p &lt; 0.0001) and Glut4 (p &lt; 0.05) mRNA expression\u2014markers of fat and glucose metabolism\u2014compared to controls. In contrast, the GAS of DOX-treated mice showed increased Cd36 (p &lt; 0.05) and Glut4 (p &lt; 0.01), together with elevated Pdk4 (p &lt; 0.001) mRNA expression\u2014suggesting reduced carbohydrate oxidation\u2014compared to controls. Additionally, DOX increased Murf1 (p &lt; 0.05) and Atrogin1 (p &lt; 0.05) mRNA expression\u2014markers of protein degradation\u2014compared to controls. In both the WAT and GAS of DOX-treated mice, Ppard mRNA expression remained unchanged. Overall, DEXRA failed to prevent these DOX-induced changes. Collectively, our results suggest that DOX induced varying degrees of wasting in adipose tissue and skeletal muscle, driven by distinct mechanisms. While DEXRA protected against DOX-induced CTRCD, it did not counteract its adverse effects on skeletal muscle and adipose tissue.<\/jats:p>","DOI":"10.3390\/ijms26031177","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T11:10:39Z","timestamp":1738149039000},"page":"1177","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Distinct Impact of Doxorubicin on Skeletal Muscle and Fat Metabolism in Mice: Without Dexrazoxane Effect"],"prefix":"10.3390","volume":"26","author":[{"given":"Birgit","family":"Van Asbroeck","sequence":"first","affiliation":[{"name":"Department of Rehabilitation Sciences & Physiotherapy, Research Group MOVANT, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium"},{"name":"Laboratory of Physiopharmacology, GENCOR, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dustin N.","family":"Kr\u00fcger","sequence":"additional","affiliation":[{"name":"Laboratory of Physiopharmacology, GENCOR, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siel","family":"Van den Bogaert","sequence":"additional","affiliation":[{"name":"Laboratory of Physiopharmacology, GENCOR, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8523-0742","authenticated-orcid":false,"given":"Dorien","family":"Dombrecht","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Sciences & Physiotherapy, Research Group MOVANT, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium"},{"name":"Laboratory of Physiopharmacology, GENCOR, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9102-5366","authenticated-orcid":false,"given":"Matthias","family":"Bosman","sequence":"additional","affiliation":[{"name":"Laboratory of Physiopharmacology, GENCOR, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7686-2668","authenticated-orcid":false,"given":"Emeline M.","family":"Van Craenenbroeck","sequence":"additional","affiliation":[{"name":"Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium"},{"name":"Department of Cardiology, Antwerp University Hospital (UZA), Drie Eikenstraat 655, B-2650 Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8640-6620","authenticated-orcid":false,"given":"Pieter-Jan","family":"Guns","sequence":"additional","affiliation":[{"name":"Laboratory of Physiopharmacology, GENCOR, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"van Breda","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Sciences & Physiotherapy, Research Group MOVANT, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1016\/j.clnu.2019.07.028","article-title":"The effects of chemotherapy on energy metabolic aspects in cancer patients: A systematic review","volume":"39","author":"Gebruers","year":"2020","journal-title":"Clin. 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