Abstract
[Purpose]Doxorubicin (DOX) is a potent anti-cancer drug that appears to have severe myotoxicity due to accumulation. The skeletal muscle has a regeneration capacity through satellite cell activation when exposed to extracellular stimulus or damage. Endurance exercise (EXE) is a therapeutic strategy that improves pathological features and contributes to muscle homeostasis. Thus, this study investigated the effect of EXE training in mitigating chronic DOX-induced myotoxicity.[Methods]Male C57BL/6J mice were housed and allowed to acclimatize with free access to food and water. All the mice were randomly divided into four groups: sedentary control (CON, n=9), exercise training (EXE, n=9), doxorubicin treatment (DOX, n=9), doxorubicin treatment and exercise training (DOX+EXE, n=9) groups. The animals were intraperitoneally injected with 5 mg/kg/week of DOX treatment for 4 weeks, and EXE training was initiated for treadmill adaptation for 1 week and then performed for 4 weeks. Both sides of the soleus (SOL) muscle tissues were dissected and weighed after 24 hours of the last training sessions.[Results]DOX chemotherapy induced an abnormal myofiber’s phenotype and transition of myosin heavy chain (MHC) isoforms. The paired box 7 (PAX7) and myoblast determination protein 1 (MYOD) protein levels were triggered by DOX, while no alterations were shown for the myogenin (MYOG). DOX remarkably impaired the a-actinin (ACTN) protein, but the EXE training seems to repair it. DOX-induced myotoxicity stimulated the expression of the forkhead box O3 (FOXO3a) protein, which was accurately controlled and adjusted by the EXE training. However, the FOXO3a-mediated downstream markers were not associated with DOX and EXE.[Conclusion]EXE postconditioning provides protective effects against chronic DOX-induced myotoxicity, and should be recommended to alleviate cancer chemotherapy-induced late-onset myotoxicity.
Highlights
Doxorubicin (DOX) is a potent chemotherapeutic agent for various cancer types, but has accompanied side effects, including fatigue and skeletal muscle weakness, leading to limitations in cancer chemotherapy[1,2]
Previous studies designed for DOX treatment and EXE training have been proposed to have positive effects regarding EXE preconditioning . 18-20,39, 44,48,49 In addition, the timing of EXE training was planned during DOX administration[41] or before and during DOX injection[43]
Several studies report that chronic DOX treatment resulted in a significant decline in body weight
Summary
Doxorubicin (DOX) is a potent chemotherapeutic agent for various cancer types, but has accompanied side effects, including fatigue and skeletal muscle weakness, leading to limitations in cancer chemotherapy[1,2]. It causes severe myotoxicity and muscle atrophy due to bioaccumulation[3,4]. The human body is made up of 40% skeletal muscle; it is one of the major tissues made up of multinucleated myofibers that possess the contractile machinery to generate force and physical activity It has plasticity, which is the ability to alter its structural and functional properties in response to exercise[23,24,25]. Some of the identified markers are expressed in each step with the recruitment of a progenitor and the myogenic regulatory factors (MRFs): paired box[7] (PAX7), myoblast determination protein 1 (MYOD), and myogenin
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