Exercise Protects Skeletal Muscle during Chronic Doxorubicin Administration

Jared M. Dickinson, Andrew C. D'Lugos, Tara N. Mahmood, Jordan C. Ormsby, Lara Salvo, W. Logan Dedmon, Shivam H. Patel, Mark S. Katsma, Farouk Mookadam, Rayna J Gonzales, Taben Hale, Chad C. Carroll, Siddhartha S. Angadi

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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% VO2peak) 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.

Original languageEnglish (US)
Pages (from-to)2394-2403
Number of pages10
JournalMedicine and Science in Sports and Exercise
Volume49
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

Doxorubicin
Skeletal Muscle
Injections
Exercise
Sirolimus
Therapeutics
Intraperitoneal Injections
Sprague Dawley Rats
Muscles
Messenger RNA
Proteins

Keywords

  • Anthracyclines
  • Autophagy
  • Exercise
  • Immunohistochemistry
  • Redd1
  • Skeletal Muscle

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Physical Therapy, Sports Therapy and Rehabilitation

Cite this

Dickinson, J. M., D'Lugos, A. C., Mahmood, T. N., Ormsby, J. C., Salvo, L., Dedmon, W. L., ... Angadi, S. S. (2017). Exercise Protects Skeletal Muscle during Chronic Doxorubicin Administration. Medicine and Science in Sports and Exercise, 49(12), 2394-2403. https://doi.org/10.1249/MSS.0000000000001395

Exercise Protects Skeletal Muscle during Chronic Doxorubicin Administration. / Dickinson, Jared M.; D'Lugos, Andrew C.; Mahmood, Tara N.; Ormsby, Jordan C.; Salvo, Lara; Dedmon, W. Logan; Patel, Shivam H.; Katsma, Mark S.; Mookadam, Farouk; Gonzales, Rayna J; Hale, Taben; Carroll, Chad C.; Angadi, Siddhartha S.

In: Medicine and Science in Sports and Exercise, Vol. 49, No. 12, 01.12.2017, p. 2394-2403.

Research output: Contribution to journalArticle

Dickinson, JM, D'Lugos, AC, Mahmood, TN, Ormsby, JC, Salvo, L, Dedmon, WL, Patel, SH, Katsma, MS, Mookadam, F, Gonzales, RJ, Hale, T, Carroll, CC & Angadi, SS 2017, 'Exercise Protects Skeletal Muscle during Chronic Doxorubicin Administration', Medicine and Science in Sports and Exercise, vol. 49, no. 12, pp. 2394-2403. https://doi.org/10.1249/MSS.0000000000001395
Dickinson JM, D'Lugos AC, Mahmood TN, Ormsby JC, Salvo L, Dedmon WL et al. Exercise Protects Skeletal Muscle during Chronic Doxorubicin Administration. Medicine and Science in Sports and Exercise. 2017 Dec 1;49(12):2394-2403. https://doi.org/10.1249/MSS.0000000000001395
Dickinson, Jared M. ; D'Lugos, Andrew C. ; Mahmood, Tara N. ; Ormsby, Jordan C. ; Salvo, Lara ; Dedmon, W. Logan ; Patel, Shivam H. ; Katsma, Mark S. ; Mookadam, Farouk ; Gonzales, Rayna J ; Hale, Taben ; Carroll, Chad C. ; Angadi, Siddhartha S. / Exercise Protects Skeletal Muscle during Chronic Doxorubicin Administration. In: Medicine and Science in Sports and Exercise. 2017 ; Vol. 49, No. 12. pp. 2394-2403.
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abstract = "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{\%} VO2peak) 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.",
keywords = "Anthracyclines, Autophagy, Exercise, Immunohistochemistry, Redd1, Skeletal Muscle",
author = "Dickinson, {Jared M.} and D'Lugos, {Andrew C.} and Mahmood, {Tara N.} and Ormsby, {Jordan C.} and Lara Salvo and Dedmon, {W. Logan} and Patel, {Shivam H.} and Katsma, {Mark S.} and Farouk Mookadam and Gonzales, {Rayna J} and Taben Hale and Carroll, {Chad C.} and Angadi, {Siddhartha S.}",
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AU - D'Lugos, Andrew C.

AU - Mahmood, Tara N.

AU - Ormsby, Jordan C.

AU - Salvo, Lara

AU - Dedmon, W. Logan

AU - Patel, Shivam H.

AU - Katsma, Mark S.

AU - Mookadam, Farouk

AU - Gonzales, Rayna J

AU - Hale, Taben

AU - Carroll, Chad C.

AU - Angadi, Siddhartha S.

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N2 - 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% VO2peak) 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.

AB - 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% VO2peak) 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.

KW - Anthracyclines

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