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Exercise Protects Skeletal Muscle during Chronic Doxorubicin Administration

DICKINSON, JARED M.1; D’LUGOS, ANDREW C.1; MAHMOOD, TARA N.1; ORMSBY, JORDAN C.1; SALVO, LARA1; DEDMON, W. LOGAN2; PATEL, SHIVAM H.2; KATSMA, MARK S.2; MOOKADAM, FAROUK3; GONZALES, RAYNA J.4; HALE, TABEN M.4; CARROLL, CHAD C.2,5; ANGADI, SIDDHARTHA S.1,3

Medicine & Science in Sports & Exercise: December 2017 - Volume 49 - Issue 12 - p 2394–2403
doi: 10.1249/MSS.0000000000001395
Basic Sciences

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% V˙O2peak) 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 mTORSer2448 and 4E-BP1Thr37/46 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, mTORSer2448, 4E-BP1Thr37/46, 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.

1School of Nutrition and Health Promotion, Healthy Lifestyles Research Center, Exercise Science and Health Promotion, Arizona State University, Phoenix, AZ; 2Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ; 3Division of Cardiovascular Diseases, Mayo Clinic Hospital, Phoenix, AZ; 4Department of Basic Medical Sciences, College of Medicine–Phoenix, University of Arizona, Phoenix, AZ; and 5Department of Health and Kinesiology, Purdue University, West Lafayette, IN

Address for correspondence: Jared M. Dickinson, Ph.D., School of Nutrition and Health Promotion, Healthy Lifestyles Research Center, Exercise Science and Health Promotion, Arizona State University, Phoenix, AZ 85004; E-mail: jared.dickinson@asu.edu.

Submitted for publication May 2017.

Accepted for publication July 2017.

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© 2017 American College of Sports Medicine