Abstract
Doxorubicin (DOX) is a chemotherapy agent widely used to treat many types of cancer; however, DOX use is limited due to its adverse effects. While cardiotoxicity is the most well-recognized issue, skeletal muscle wasting and weakness is another significant adverse effect that can decrease quality of life, manifested clinically through weakness and exercise intolerance. PURPOSE: We aimed to investigate the effects of DOX treatment on exercise intolerance and muscle function in preclinical models of both acute and chronic effects of chemotherapy using non-tumor-bearing rats. We also investigated the preventive and therapeutic effects of endurance training in these models. METHODS: 55 male Wistar rats were split into two studies: acute (A; n=28) and chronic (C; n=27). Four groups were constituted per study: control sedentary (CS), control exercise (CE), DOX sedentary (DOXS), and DOX exercise (DOXE). For the acute study (A), CE-A and DOXE-A groups were subjected to a preconditioning endurance training (treadmill run 60% max capacity 5d/wk for 4 wks). Following training period, DOXS-A and DOXE-A groups received a single DOX injection (20mg/kg) while control rats received saline solution and were euthanized 48h after the injections. For the chronic study (C), DOX groups (DOXS-C and DOXE-C) received 4 DOX injections (4mg/kg/week) concomitantly with endurance training (groups CE-C and DOXE-C). Animals were euthanized 48h after the last exercise session. All rats completed in vivo functional experiments before euthanasia and had blood collected for the measurement of tumor necrosis factor-alpha [TNF-alpha]. RESULTS: DOX treatment caused exercise intolerance chronically (pDOX=0.0095) but not acutely. Endurance training improved exercise tolerance (Acute: pETpET=0.0005). Regarding muscle function, rats treated with DOX showed a higher muscle torque than controls in the acute phase (pDOXpDOX=0.0114; pI=0.0401), observed only in sedentary animals. Finally, we found circulating levels of TNF-alpha increased in DOX-treated animals at the acute (pDOXCONCLUSION: Our data suggest that the increased contractility at the acute phase of DOX chemotherapy may be due a compensatory mechanism (such as TNF-alpha-induced Ca2+ release), which chronically led to a reduction in muscle function. Endurance training seemed to partially protect the chronic effect of DOX on muscle function. Further analyzes are needed to investigate the mechanisms behind DOX-induced muscle dysfunction.
Recommended Citation
Pigg, Quinten W.; Harris, Dillon; Sayuri Inoue, Daniela; Polegato, Bertha F.; Tonon, Carol R.; and Janini Gomes, Mariana
(2025)
"Acute vs. Chronic Response to Doxorubicin Treatment with Endurance Training in Non-Tumor-Bearing Rats,"
International Journal of Exercise Science: Conference Proceedings: Vol. 2:
Iss.
17, Article 105.
Available at:
https://digitalcommons.wku.edu/ijesab/vol2/iss17/105
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Health and Physical Education Commons, Medical Education Commons, Sports Sciences Commons