Exercise Protects Skeletal Muscle during Chronic Doxorubicin Administration.

PURPOSE: To assess the ability for exercise training performed before and during bi-weekly doxorubicin (DOX) administration to attenuate adverse effects of DOX on skeletal muscle. We hypothesized that DOX treatment would increase REDD1, impair mammalian target of rapamycin (mTOR) signaling, and reduce muscle fiber size, and that exercise training would attenuate these responses. METHODS: Eight-week old ovariectomized female Sprague-Dawley rats were randomized to one of four treatments: Exercise+DOX (Ex-Dox); Ex+Vehicle (Ex-Veh), Sedentary+DOX (Sed-Dox); and Sed+Veh (Sed-Veh). DOX (4mg/kg) or vehicle (saline) intraperitoneal injections were performed bi-weekly for a total of 3 injections (cumulative dose 12mg/kg). Ex animals performed interval exercise (4x4min, 85-90 %VO2peak) 5d/week starting one week prior to the first injection and continued throughout study duration. Animals were euthanized ~5d following the last injection, during which the soleus muscle was dissected and prepared for immunoblot and immunohistochemical analyses. RESULTS: REDD1 mRNA and protein were increased only in Sed-Dox (P0.05). LC3BI was higher and the LC3BII/I ratio was lower in Sed-Dox vs. Sed-Veh (P0.05). CONCLUSION: These data suggest that DOX may inhibit mTORC1 activity and reduce MHCI and MHCIIa fiber size, potentially through elevated REDD1, and that exercise may provide a therapeutic strategy to preserve skeletal muscle size during chronic DOX treatment. (C) 2017 American College of Sports Medicine

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