Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle.

Gilles Gouspillou,Sally Spendiff,Heather Mlynarski,Tanja Taivassalo,Elodie Archer-Lahlou,Stéphanie Chevalier,Madhusudanarao Vuda,Celena Scheede-Bergdahl,Fennigje M Purves-Smith,Janusz Rak,R Thomas Jagoe,Brian Meehan,Yana Konokhova,Nicolas Sgarioto,Russell T Hepple

doi:10.1038/srep08717

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.

Highlights

Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle
We have shown that administration of four cycles of doxorubicin and dexamethasone induces a progressive inhibition of growth that becomes irreversible after the fourth cycle of treatment in nontumor-bearing mice
In light of prior data showing that anthracycline toxicity in cardiac muscle is closely linked to mitochondrial dysfunction, we studied the effects of the dexamethasone and doxorubicin treatment on mitochondrial function in skeletal muscle

Summary

Introduction

Anthracycline-containing chemotherapy causes long-term impairment of mitochondrial respiration and increased reactive oxygen species release in skeletal muscle. Anticancer treatments for childhood acute lymphoblastic leukaemia (ALL) are highly effective but are implicated in causing impaired muscle function in long-term survivors. 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 chemotherapy agents used as part of the anti-ALL treatment are implicated as one of the likely causes for these long-term effects in skeletal muscle, including reduced muscle mass and function (reviewed in Ref. 4). It still remains to be determined whether skeletal muscle mitochondria demonstrate any long-term functional impairment after anthracycline treatment, and if so what mechanisms may be involved

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Results

Conclusion