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 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.
1] McGill University Health Centre, Montreal, Quebec, Canada [2] Département de Kinanthropologie, Université du Québec à Montréal, Montreal, Quebec, Canada.
Gilles
G
Gouspillou
1] Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada [2] Department of Kinesiology, McGill University, Montreal, Quebec, Canada.
Celena
C
Scheede-Bergdahl
1] McGill University Health Centre, Montreal, Quebec, Canada [2] Department of Kinesiology, McGill University, Montreal, Quebec, Canada.
Sally
S
Spendiff
McGill University Health Centre, Montreal, Quebec, Canada.
Madhusudanarao
M
Vuda
1] Department of Oncology, McGill University, Montreal, Quebec, Canada [2] Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada.
Brian
B
Meehan
Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Heather
H
Mlynarski
Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Elodie
E
Archer-Lahlou
McGill University Health Centre, Montreal, Quebec, Canada.
Nicolas
N
Sgarioto
1] McGill University Health Centre, Montreal, Quebec, Canada [2] Department of Kinesiology, McGill University, Montreal, Quebec, Canada.
Fennigje M
FM
Purves-Smith
1] McGill University Health Centre, Montreal, Quebec, Canada [2] Department of Kinesiology, McGill University, Montreal, Quebec, Canada.
Yana
Y
Konokhova
1] Department of Oncology, McGill University, Montreal, Quebec, Canada [2] Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada.
Janusz
J
Rak
McGill University Health Centre, Montreal, Quebec, Canada.
Stéphanie
S
Chevalier
Department of Kinesiology, McGill University, Montreal, Quebec, Canada.
Tanja
T
Taivassalo
1] McGill University Health Centre, Montreal, Quebec, Canada [2] Department of Kinesiology, McGill University, Montreal, Quebec, Canada.
Russell T
RT
Hepple
1] Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada [2] Department of Oncology, McGill University, Montreal, Quebec, Canada.
R Thomas
RT
Jagoe
D000818:Animals; D018943:Anthracyclines / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects; D004272:DNA, Mitochondrial; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D051379:Mice; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017384:Sequence Deletion
D018943:Anthracyclines; D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D003907:Dexamethasone; D004317:Doxorubicin