Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle
Gilles Gouspillou, Celena Scheede-Bergdahl, Sally Spendiff, Madhusudanarao Vuda, Brian Meehan, Heather Mlynarski, Elodie Archer-Lahlou, Nicolas Sgarioto, Fennigje M Purves-Smith, Yana Konokhova, Janusz Rak, Stéphanie Chevalier, Tanja Taivassalo, Russell T Hepple, R Thomas Jagoe, Gilles Gouspillou, Celena Scheede-Bergdahl, Sally Spendiff, Madhusudanarao Vuda, Brian Meehan, Heather Mlynarski, Elodie Archer-Lahlou, Nicolas Sgarioto, Fennigje M Purves-Smith, Yana Konokhova, Janusz Rak, Stéphanie Chevalier, Tanja Taivassalo, Russell T Hepple, R Thomas Jagoe
Abstract
Anticancer treatments for childhood acute lymphoblastic leukaemia (ALL) are highly effective but are now implicated in causing impaired muscle function in long-term survivors. However, no comprehensive assessment of skeletal muscle mitochondrial functions in long-term survivors has been performed and the presence of persistent chemotherapy-induced skeletal muscle mitochondrial dysfunction remains a strong possibility. Non-tumour-bearing mice were treated with two drugs that have been used frequently in ALL treatment (doxorubicin and dexamethasone) for up to 4 cycles at 3-week intervals and euthanized 3 months after the 4th cycle. Treated animals had impaired growth and lower muscle mass as well as reduced mitochondrial respiration and increased reactive oxygen species production per unit oxygen consumption. Mitochondrial DNA content and protein levels of key mitochondrial membrane proteins and markers of mitochondrial biogenesis were unchanged, but protein levels of Parkin were reduced. This suggests a novel pattern of chemotherapy-induced mitochondrial dysfunction in skeletal muscle that persists because of an acquired defect in mitophagy signaling. The results could explain the observed functional impairments in adult survivors of childhood ALL and may also be relevant to long-term survivors of other cancers treated with similar regimes.
Figures
![Figure 1. Chemotherapy treatment causes sustained impairment…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4346812/bin/srep08717-f1.jpg)
Figure 2. Chemotherapy treatment causes generalized chronic…
Figure 2. Chemotherapy treatment causes generalized chronic impairment in skeletal muscle mitochondrial function.
(A, B)…
Figure 3. Chemotherapy treatment-induced chronic intrinsic mitochondrial…
Figure 3. Chemotherapy treatment-induced chronic intrinsic mitochondrial functional changes in skeletal muscle are not mediated…
Figure 4. Altered mitochondrial quality control mechanisms…
Figure 4. Altered mitochondrial quality control mechanisms rather than increased cellular oxidative damage are implicated…
- Hyperammonaemia-induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress.Davuluri G, Allawy A, Thapaliya S, Rennison JH, Singh D, Kumar A, Sandlers Y, Van Wagoner DR, Flask CA, Hoppel C, Kasumov T, Dasarathy S. Davuluri G, et al. J Physiol. 2016 Dec 15;594(24):7341-7360. doi: 10.1113/JP272796. Epub 2016 Oct 23. J Physiol. 2016. PMID: 27558544 Free PMC article.
- Targeted overexpression of mitochondrial catalase protects against cancer chemotherapy-induced skeletal muscle dysfunction.Gilliam LA, Lark DS, Reese LR, Torres MJ, Ryan TE, Lin CT, Cathey BL, Neufer PD. Gilliam LA, et al. Am J Physiol Endocrinol Metab. 2016 Aug 1;311(2):E293-301. doi: 10.1152/ajpendo.00540.2015. Epub 2016 Jun 21. Am J Physiol Endocrinol Metab. 2016. PMID: 27329802 Free PMC article.
- The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle.Gilliam LAA, Fisher-Wellman KH, Lin CT, Maples JM, Cathey BL, Neufer PD. Gilliam LAA, et al. Free Radic Biol Med. 2013 Dec;65:988-996. doi: 10.1016/j.freeradbiomed.2013.08.191. Epub 2013 Sep 7. Free Radic Biol Med. 2013. PMID: 24017970 Free PMC article.
- Oxidative stress mediates ethanol-induced skeletal muscle mitochondrial dysfunction and dysregulated protein synthesis and autophagy.Kumar A, Davuluri G, Welch N, Kim A, Gangadhariah M, Allawy A, Priyadarshini A, McMullen MR, Sandlers Y, Willard B, Hoppel CL, Nagy LE, Dasarathy S. Kumar A, et al. Free Radic Biol Med. 2019 Dec;145:284-299. doi: 10.1016/j.freeradbiomed.2019.09.031. Epub 2019 Sep 28. Free Radic Biol Med. 2019. PMID: 31574345 Free PMC article.
- Impact of aging on mitochondrial function in cardiac and skeletal muscle.Hepple RT. Hepple RT. Free Radic Biol Med. 2016 Sep;98:177-186. doi: 10.1016/j.freeradbiomed.2016.03.017. Epub 2016 Mar 24. Free Radic Biol Med. 2016. PMID: 27033952 Review.
- Chemotherapy-Induced Molecular Changes in Skeletal Muscle.Pedrosa MB, Barbosa S, Vitorino R, Ferreira R, Moreira-Gonçalves D, Santos LL. Pedrosa MB, et al. Biomedicines. 2023 Mar 15;11(3):905. doi: 10.3390/biomedicines11030905. Biomedicines. 2023. PMID: 36979884 Free PMC article. Review.
- Chemotherapy impairs skeletal muscle mitochondrial homeostasis in early breast cancer patients.Mallard J, Hucteau E, Charles AL, Bender L, Baeza C, Pélissie M, Trensz P, Pflumio C, Kalish-Weindling M, Gény B, Schott R, Favret F, Pivot X, Hureau TJ, Pagano AF. Mallard J, et al. J Cachexia Sarcopenia Muscle. 2022 Jun;13(3):1896-1907. doi: 10.1002/jcsm.12991. Epub 2022 Apr 4. J Cachexia Sarcopenia Muscle. 2022. PMID: 35373507 Free PMC article.
- Greenspace, Inflammation, Cardiovascular Health, and Cancer: A Review and Conceptual Framework for Greenspace in Cardio-Oncology Research.Bikomeye JC, Beyer AM, Kwarteng JL, Beyer KMM. Bikomeye JC, et al. Int J Environ Res Public Health. 2022 Feb 19;19(4):2426. doi: 10.3390/ijerph19042426. Int J Environ Res Public Health. 2022. PMID: 35206610 Free PMC article. Review.
- Skeletal Muscle Deconditioning in Breast Cancer Patients Undergoing Chemotherapy: Current Knowledge and Insights From Other Cancers.Mallard J, Hucteau E, Hureau TJ, Pagano AF. Mallard J, et al. Front Cell Dev Biol. 2021 Sep 14;9:719643. doi: 10.3389/fcell.2021.719643. eCollection 2021. Front Cell Dev Biol. 2021. PMID: 34595171 Free PMC article. Review.
- Association of Cardiotoxicity With Doxorubicin and Trastuzumab: A Double-Edged Sword in Chemotherapy.Gabani M, Castañeda D, Nguyen QM, Choi SK, Chen C, Mapara A, Kassan A, Gonzalez AA, Khataei T, Ait-Aissa K, Kassan M. Gabani M, et al. Cureus. 2021 Sep 22;13(9):e18194. doi: 10.7759/cureus.18194. eCollection 2021 Sep. Cureus. 2021. PMID: 34589374 Free PMC article. Review.
-
- Siegel R., Naishadham D. & Jemal A. Cancer statistics, 2012. CA Cancer J Clin 62, 10–29 (2012). - PubMed
-
- Zuelzer W. W. Implications of long-term survival in acute stem cell leukemia of childhood treated with composite cyclical therapy. Blood 24, 477–494 (1964). - PubMed
-
- Pui C.-H. & Evans W. E. Treatment of acute lymphoblastic leukemia. N Engl J Med 354, 166–178 (2006). - PubMed
- Research Support, Non-U.S. Gov't
- Animals
- Anthracyclines / administration & dosage
- Anthracyclines / pharmacology*
- Antineoplastic Agents / administration & dosage
- Antineoplastic Agents / pharmacology*
- Cell Respiration / drug effects
- DNA, Mitochondrial
- Dexamethasone / administration & dosage
- Dexamethasone / pharmacology
- Doxorubicin / administration & dosage
- Doxorubicin / pharmacology
- Female
- Mice
- Mitochondria, Muscle / drug effects*
- Mitochondria, Muscle / genetics
- Mitochondria, Muscle / metabolism*
- Mitophagy / drug effects
- Muscle, Skeletal / drug effects*
- Muscle, Skeletal / metabolism*
- Muscle, Skeletal / pathology
- Mutation
- Oxidative Stress
- Reactive Oxygen Species / metabolism*
- Sequence Deletion
- Anthracyclines
- Antineoplastic Agents
- DNA, Mitochondrial
- Reactive Oxygen Species
- Dexamethasone
- Doxorubicin
- Full Text Sources
- Other Literature Sources
- Medical
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![Figure 2. Chemotherapy treatment causes generalized chronic…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4346812/bin/srep08717-f2.jpg)
![Figure 3. Chemotherapy treatment-induced chronic intrinsic mitochondrial…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4346812/bin/srep08717-f3.jpg)
Figure 4. Altered mitochondrial quality control mechanisms…
Figure 4. Altered mitochondrial quality control mechanisms rather than increased cellular oxidative damage are implicated…
- Hyperammonaemia-induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress.Davuluri G, Allawy A, Thapaliya S, Rennison JH, Singh D, Kumar A, Sandlers Y, Van Wagoner DR, Flask CA, Hoppel C, Kasumov T, Dasarathy S. Davuluri G, et al. J Physiol. 2016 Dec 15;594(24):7341-7360. doi: 10.1113/JP272796. Epub 2016 Oct 23. J Physiol. 2016. PMID: 27558544 Free PMC article.
- Targeted overexpression of mitochondrial catalase protects against cancer chemotherapy-induced skeletal muscle dysfunction.Gilliam LA, Lark DS, Reese LR, Torres MJ, Ryan TE, Lin CT, Cathey BL, Neufer PD. Gilliam LA, et al. Am J Physiol Endocrinol Metab. 2016 Aug 1;311(2):E293-301. doi: 10.1152/ajpendo.00540.2015. Epub 2016 Jun 21. Am J Physiol Endocrinol Metab. 2016. PMID: 27329802 Free PMC article.
- The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle.Gilliam LAA, Fisher-Wellman KH, Lin CT, Maples JM, Cathey BL, Neufer PD. Gilliam LAA, et al. Free Radic Biol Med. 2013 Dec;65:988-996. doi: 10.1016/j.freeradbiomed.2013.08.191. Epub 2013 Sep 7. Free Radic Biol Med. 2013. PMID: 24017970 Free PMC article.
- Oxidative stress mediates ethanol-induced skeletal muscle mitochondrial dysfunction and dysregulated protein synthesis and autophagy.Kumar A, Davuluri G, Welch N, Kim A, Gangadhariah M, Allawy A, Priyadarshini A, McMullen MR, Sandlers Y, Willard B, Hoppel CL, Nagy LE, Dasarathy S. Kumar A, et al. Free Radic Biol Med. 2019 Dec;145:284-299. doi: 10.1016/j.freeradbiomed.2019.09.031. Epub 2019 Sep 28. Free Radic Biol Med. 2019. PMID: 31574345 Free PMC article.
- Impact of aging on mitochondrial function in cardiac and skeletal muscle.Hepple RT. Hepple RT. Free Radic Biol Med. 2016 Sep;98:177-186. doi: 10.1016/j.freeradbiomed.2016.03.017. Epub 2016 Mar 24. Free Radic Biol Med. 2016. PMID: 27033952 Review.
- Chemotherapy-Induced Molecular Changes in Skeletal Muscle.Pedrosa MB, Barbosa S, Vitorino R, Ferreira R, Moreira-Gonçalves D, Santos LL. Pedrosa MB, et al. Biomedicines. 2023 Mar 15;11(3):905. doi: 10.3390/biomedicines11030905. Biomedicines. 2023. PMID: 36979884 Free PMC article. Review.
- Chemotherapy impairs skeletal muscle mitochondrial homeostasis in early breast cancer patients.Mallard J, Hucteau E, Charles AL, Bender L, Baeza C, Pélissie M, Trensz P, Pflumio C, Kalish-Weindling M, Gény B, Schott R, Favret F, Pivot X, Hureau TJ, Pagano AF. Mallard J, et al. J Cachexia Sarcopenia Muscle. 2022 Jun;13(3):1896-1907. doi: 10.1002/jcsm.12991. Epub 2022 Apr 4. J Cachexia Sarcopenia Muscle. 2022. PMID: 35373507 Free PMC article.
- Greenspace, Inflammation, Cardiovascular Health, and Cancer: A Review and Conceptual Framework for Greenspace in Cardio-Oncology Research.Bikomeye JC, Beyer AM, Kwarteng JL, Beyer KMM. Bikomeye JC, et al. Int J Environ Res Public Health. 2022 Feb 19;19(4):2426. doi: 10.3390/ijerph19042426. Int J Environ Res Public Health. 2022. PMID: 35206610 Free PMC article. Review.
- Skeletal Muscle Deconditioning in Breast Cancer Patients Undergoing Chemotherapy: Current Knowledge and Insights From Other Cancers.Mallard J, Hucteau E, Hureau TJ, Pagano AF. Mallard J, et al. Front Cell Dev Biol. 2021 Sep 14;9:719643. doi: 10.3389/fcell.2021.719643. eCollection 2021. Front Cell Dev Biol. 2021. PMID: 34595171 Free PMC article. Review.
- Association of Cardiotoxicity With Doxorubicin and Trastuzumab: A Double-Edged Sword in Chemotherapy.Gabani M, Castañeda D, Nguyen QM, Choi SK, Chen C, Mapara A, Kassan A, Gonzalez AA, Khataei T, Ait-Aissa K, Kassan M. Gabani M, et al. Cureus. 2021 Sep 22;13(9):e18194. doi: 10.7759/cureus.18194. eCollection 2021 Sep. Cureus. 2021. PMID: 34589374 Free PMC article. Review.
-
- Siegel R., Naishadham D. & Jemal A. Cancer statistics, 2012. CA Cancer J Clin 62, 10–29 (2012). - PubMed
-
- Zuelzer W. W. Implications of long-term survival in acute stem cell leukemia of childhood treated with composite cyclical therapy. Blood 24, 477–494 (1964). - PubMed
-
- Pui C.-H. & Evans W. E. Treatment of acute lymphoblastic leukemia. N Engl J Med 354, 166–178 (2006). - PubMed
- Research Support, Non-U.S. Gov't
- Animals
- Anthracyclines / administration & dosage
- Anthracyclines / pharmacology*
- Antineoplastic Agents / administration & dosage
- Antineoplastic Agents / pharmacology*
- Cell Respiration / drug effects
- DNA, Mitochondrial
- Dexamethasone / administration & dosage
- Dexamethasone / pharmacology
- Doxorubicin / administration & dosage
- Doxorubicin / pharmacology
- Female
- Mice
- Mitochondria, Muscle / drug effects*
- Mitochondria, Muscle / genetics
- Mitochondria, Muscle / metabolism*
- Mitophagy / drug effects
- Muscle, Skeletal / drug effects*
- Muscle, Skeletal / metabolism*
- Muscle, Skeletal / pathology
- Mutation
- Oxidative Stress
- Reactive Oxygen Species / metabolism*
- Sequence Deletion
- Anthracyclines
- Antineoplastic Agents
- DNA, Mitochondrial
- Reactive Oxygen Species
- Dexamethasone
- Doxorubicin
- Full Text Sources
- Other Literature Sources
- Medical
![Figure 4. Altered mitochondrial quality control mechanisms…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4346812/bin/srep08717-f4.jpg)
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