Exercise Protects Skeletal Muscle during Chronic Doxorubicin Administration

Purpose This study aimed to assess the ability for exercise training performed before and during biweekly 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 (4 mg·kg^-1) or vehicle (saline) intraperitoneal injections were performed biweekly for a total of three injections (cumulative dose, 12 mg·kg^-1). Ex animals performed interval exercise (4 × 4 min, 85%-90% VO_2peak) 5 d·wk^-1 starting 1 wk before the first injection and continued throughout study duration. Animals were euthanized 5 d after 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 (P < 0.05). The phosphorylation of mTOR^Ser2448 and 4E-BP1^Thr37/46 and MHC I and MHC IIa fiber size were lower in Sed-Dox versus Sed-Veh (P < 0.05). By contrast, REDD1 mRNA and protein, mTOR^Ser2448, 4E-BP1^Thr37/46, and MHC I fiber size were not different between Ex-Dox and Ex-Veh (P > 0.05). LC3BI was higher, and the LC3BII/I ratio was lower in Sed-Dox versus Sed-Veh (P < 0.05) but not between Ex-Dox and Ex-Veh (P > 0.05). 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.