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

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34 Scopus citations

Abstract

Anticancer treatments for childhood acute lymphoblastic leukaemia (ALL) are highly effective but are now implicated in causing impairedmuscle 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 lowermusclemass aswell 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 inmitophagy 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.
Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalScientific Reports
DOIs
StatePublished - 2015

Keywords

  • Anticancer treatments
  • Chemotherapy
  • Doxorubicin
  • Reactive Oxygen Species
  • dexamethasone
  • lymphoblastic leukaemia
  • mitochondrial dysfunction

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    Gouspillou, G., Scheede-Bergdahl, C., Spendiff, S., Vuda, M., Meehan, B., Mlynarski, H., Archer-Lahlou, E., Sgarioto, N., Purves-Smith, F. M., Konokhova, Y., Rak, J., Chevalier, S., Taivassalo, T., Hepple, R. T., & Jagoe, R. T. (2015). Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle. Scientific Reports, 1-10. https://doi.org/10.1038/srep08717