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Hydock, David S.

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Doxorubicin (DOX) is a widely used anthracycline antibiotic used to treat a number of hematological and solid tumor cancers. Dosage; however, is limited due to its toxic effects in healthy tissues. Negative consequences include myotoxicity in skeletal muscle, which may limit mobility and activities of daily living. The capacity for skeletal muscular regeneration relies heavily of the activity of myogenic regulatory factor (MRF) proteins. In vitro experiments with DOX depress expression of MRFs but in vivo treatment may elicit different responses. Endurance exercise has been shown to elevate MRF expression, and may preserve MRFs following in vivo DOX-treatment. Purpose: To determine the effect of short-term endurance training and acute DOX administration of skeletal muscle force production and fatigue resistance, levels of lipid peroxidation, and expression of MRFs. Methods: Ten week old male Sprague-Dawley rats were randomly assigned to one of four groups: sedentary + saline (SED-SAL), SED- DOX, endurance exercise training + saline (EXER-SAL), or EXER-DOX. Animals remained sedentary or performed treadmill training for two weeks. Twenty four hours after the activity period, animals were injected with a bolus 15 mg/kg i.p. injection of DOX or SAL. Twenty four hours after injection, soleus (SOL) and extensor digitorum longus (EDL) skeletal muscles were removed for ex vivo function measures. Analyses of lipid peroxidation as malondialdehyde and 4-hydroxyalkenals (MDA + 4-HAE) and Western blotting for concentration for MRFs (Myf5, MyoD, myogenin, Mrf4) were performed on contralateral muscles. Results: Endurance exercise significantly elevated Myf5 and Mrf4 in the SOL (p<0.05). No significant differences existed in MRF expression levels in the EDL. No significant muscle force production or fatigue resistance differences were identified due to drug or activity treatment. MDA + 4-HAE was higher in the SOL of SAL animals (p<0.05) and EDL of EXER animals (p<0.05). Conclusion: Short-term endurance exercise effectively elevated Myf5 and Mrf4 in slow, oxidative muscle after acute DOX treatment. Endurance exercise prior to chemotherapy may augment skeletal muscles’ regenerative capacity following treatment, when loss of muscle mass is common.


Aerobic, Doxorubicin, Exercise, Myogenesis, Skeletal muscle


128 pages

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