Exercise training partly ameliorates cardiac dysfunction in mice during doxorubicin treatment of breast cancer

Tytti-Maria Uurasmaa; Pauline Bourdin; Wail Nammas; Shiva Latifi; Heidi Liljenbäck; Antti Saraste; Olli Eskola; Johan Rajander; Anne Roivainen; Helene Rundqvist; Anu Autio; Ilkka Heinonen; Katja Anttila

doi:10.1186/s12967-025-06108-y

Exercise training partly ameliorates cardiac dysfunction in mice during doxorubicin treatment of breast cancer

Tytti-Maria Uurasmaa, Pauline Bourdin, Wail Nammas, Shiva Latifi, Heidi Liljenbäck, Antti Saraste, Olli Eskola, Johan Rajander, Anne Roivainen, Helene Rundqvist, Anu Autio, Ilkka Heinonen, Katja Anttila

Turku PET Centre

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Abstract

INTRODUCTION: Doxorubicin is a chemotherapeutic drug used to treat various cancers. Exercise training (ET) can attenuate some cardiotoxic effects of doxorubicin (DOX) in tumor-free animals. However, the ET effects on cardiac function and glucose metabolism in DOX-treated breast cancer models remain unclear.

OBJECTIVES: This study investigated ET-induced structural, functional, vascular, oxidative stress, and plausible glucose uptake alterations of the left ventricle (LV) in a murine breast cancer model during DOX treatment.

METHODS: Female FVB/N-mice were divided to tumor-free groups with or without voluntary wheel-running ET and those inoculated subcutaneously with mammary tumor-derived I3TC-cells with or without exercise or DOX treatment (5 mg/kg/week). Mice underwent 2-[ 18F]fluoro-2-deoxy-D-glucose positron emission tomography and echocardiography after two and four DOX-doses. The cardiac histology, oxidative stress, maximal metabolic enzyme activities, and mitochondrial respiration were analyzed.

RESULTS: DOX increased LV glucose uptake (LVGU) and mitochondrial uncoupling and decreased running activity, LV-weight, and ejection fraction (EF). In DOX-treated group ET blunted the increase in LVGU, increased LV-weight and EF, and lowered LV lactate dehydrogenase activity. DOX-treated exercised mice did not differ from tumor-bearing group without DOX in LVGU or from the tumor-free ET-group in LV-weight or EF whereas unexercised DOX-treated group did. ET also increased LV citrate synthase activity in tumor-bearing animals. There was an inverse association between LVGU and EF and LV-weight.

CONCLUSION: In a murine breast cancer model, voluntary ET moderated DOX-induced cardiotoxicities such as increased LVGU, LV-atrophy and decreased EF. This suggests that ET might benefit patients with cancer undergoing doxorubicin treatment by mitigating cardiotoxicity.

Original language	English
Article number	89
Journal	Journal of Translational Medicine
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s12967-025-06108-y
Publication status	Published - 21 Jan 2025
MoE publication type	A1 Journal article-refereed

Funding

Turku University Foundation, Research Council of Finland (#350315, #350117), Finnish Physiological Society, Lounaissuomalaiset Sy\u00F6p\u00E4j\u00E4rjest\u00F6t, Jane and Aatos Erkko Foundation, Finnish Foundation for Cardiovascular Research, and State Research Funding of the Turku University Hospital. We would like to thank the staff of University of Turku Central Animal Laboratory and the staff of University of Turku PET Centre for animal care and imaging, respectively. We would like to extend a special thank you to PET camera controller Aake Petteri Honkaniemi for his invaluable help with PET-imaging.

Keywords

Animals
Doxorubicin/adverse effects
Female
Physical Conditioning, Animal
Breast Neoplasms/pathology
Oxidative Stress/drug effects
Mice
Glucose/metabolism
Cell Line, Tumor
Heart Ventricles/drug effects
Positron-Emission Tomography

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10.1186/s12967-025-06108-y

s12967-025-06108-yFinal published version, 4.14 MBLicence: CC BY

https://urn.fi/URN:NBN:fi-fe2025042831658

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Uurasmaa, T.-M., Bourdin, P., Nammas, W., Latifi, S., Liljenbäck, H., Saraste, A., Eskola, O., Rajander, J., Roivainen, A., Rundqvist, H., Autio, A., Heinonen, I., & Anttila, K. (2025). Exercise training partly ameliorates cardiac dysfunction in mice during doxorubicin treatment of breast cancer. Journal of Translational Medicine, 23(1), Article 89. https://doi.org/10.1186/s12967-025-06108-y

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title = "Exercise training partly ameliorates cardiac dysfunction in mice during doxorubicin treatment of breast cancer",

abstract = "INTRODUCTION: Doxorubicin is a chemotherapeutic drug used to treat various cancers. Exercise training (ET) can attenuate some cardiotoxic effects of doxorubicin (DOX) in tumor-free animals. However, the ET effects on cardiac function and glucose metabolism in DOX-treated breast cancer models remain unclear.OBJECTIVES: This study investigated ET-induced structural, functional, vascular, oxidative stress, and plausible glucose uptake alterations of the left ventricle (LV) in a murine breast cancer model during DOX treatment.METHODS: Female FVB/N-mice were divided to tumor-free groups with or without voluntary wheel-running ET and those inoculated subcutaneously with mammary tumor-derived I3TC-cells with or without exercise or DOX treatment (5 mg/kg/week). Mice underwent 2-[ 18F]fluoro-2-deoxy-D-glucose positron emission tomography and echocardiography after two and four DOX-doses. The cardiac histology, oxidative stress, maximal metabolic enzyme activities, and mitochondrial respiration were analyzed. RESULTS: DOX increased LV glucose uptake (LVGU) and mitochondrial uncoupling and decreased running activity, LV-weight, and ejection fraction (EF). In DOX-treated group ET blunted the increase in LVGU, increased LV-weight and EF, and lowered LV lactate dehydrogenase activity. DOX-treated exercised mice did not differ from tumor-bearing group without DOX in LVGU or from the tumor-free ET-group in LV-weight or EF whereas unexercised DOX-treated group did. ET also increased LV citrate synthase activity in tumor-bearing animals. There was an inverse association between LVGU and EF and LV-weight.CONCLUSION: In a murine breast cancer model, voluntary ET moderated DOX-induced cardiotoxicities such as increased LVGU, LV-atrophy and decreased EF. This suggests that ET might benefit patients with cancer undergoing doxorubicin treatment by mitigating cardiotoxicity.",

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author = "Tytti-Maria Uurasmaa and Pauline Bourdin and Wail Nammas and Shiva Latifi and Heidi Liljenb{\"a}ck and Antti Saraste and Olli Eskola and Johan Rajander and Anne Roivainen and Helene Rundqvist and Anu Autio and Ilkka Heinonen and Katja Anttila",

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doi = "10.1186/s12967-025-06108-y",

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Uurasmaa, T-M, Bourdin, P, Nammas, W, Latifi, S, Liljenbäck, H, Saraste, A, Eskola, O, Rajander, J, Roivainen, A, Rundqvist, H, Autio, A, Heinonen, I & Anttila, K 2025, 'Exercise training partly ameliorates cardiac dysfunction in mice during doxorubicin treatment of breast cancer', Journal of Translational Medicine, vol. 23, no. 1, 89. https://doi.org/10.1186/s12967-025-06108-y

TY - JOUR

T1 - Exercise training partly ameliorates cardiac dysfunction in mice during doxorubicin treatment of breast cancer

AU - Uurasmaa, Tytti-Maria

AU - Bourdin, Pauline

AU - Nammas, Wail

AU - Latifi, Shiva

AU - Liljenbäck, Heidi

AU - Saraste, Antti

AU - Eskola, Olli

AU - Rajander, Johan

AU - Roivainen, Anne

AU - Rundqvist, Helene

AU - Autio, Anu

AU - Heinonen, Ilkka

AU - Anttila, Katja

PY - 2025/1/21

Y1 - 2025/1/21

N2 - INTRODUCTION: Doxorubicin is a chemotherapeutic drug used to treat various cancers. Exercise training (ET) can attenuate some cardiotoxic effects of doxorubicin (DOX) in tumor-free animals. However, the ET effects on cardiac function and glucose metabolism in DOX-treated breast cancer models remain unclear.OBJECTIVES: This study investigated ET-induced structural, functional, vascular, oxidative stress, and plausible glucose uptake alterations of the left ventricle (LV) in a murine breast cancer model during DOX treatment.METHODS: Female FVB/N-mice were divided to tumor-free groups with or without voluntary wheel-running ET and those inoculated subcutaneously with mammary tumor-derived I3TC-cells with or without exercise or DOX treatment (5 mg/kg/week). Mice underwent 2-[ 18F]fluoro-2-deoxy-D-glucose positron emission tomography and echocardiography after two and four DOX-doses. The cardiac histology, oxidative stress, maximal metabolic enzyme activities, and mitochondrial respiration were analyzed. RESULTS: DOX increased LV glucose uptake (LVGU) and mitochondrial uncoupling and decreased running activity, LV-weight, and ejection fraction (EF). In DOX-treated group ET blunted the increase in LVGU, increased LV-weight and EF, and lowered LV lactate dehydrogenase activity. DOX-treated exercised mice did not differ from tumor-bearing group without DOX in LVGU or from the tumor-free ET-group in LV-weight or EF whereas unexercised DOX-treated group did. ET also increased LV citrate synthase activity in tumor-bearing animals. There was an inverse association between LVGU and EF and LV-weight.CONCLUSION: In a murine breast cancer model, voluntary ET moderated DOX-induced cardiotoxicities such as increased LVGU, LV-atrophy and decreased EF. This suggests that ET might benefit patients with cancer undergoing doxorubicin treatment by mitigating cardiotoxicity.

AB - INTRODUCTION: Doxorubicin is a chemotherapeutic drug used to treat various cancers. Exercise training (ET) can attenuate some cardiotoxic effects of doxorubicin (DOX) in tumor-free animals. However, the ET effects on cardiac function and glucose metabolism in DOX-treated breast cancer models remain unclear.OBJECTIVES: This study investigated ET-induced structural, functional, vascular, oxidative stress, and plausible glucose uptake alterations of the left ventricle (LV) in a murine breast cancer model during DOX treatment.METHODS: Female FVB/N-mice were divided to tumor-free groups with or without voluntary wheel-running ET and those inoculated subcutaneously with mammary tumor-derived I3TC-cells with or without exercise or DOX treatment (5 mg/kg/week). Mice underwent 2-[ 18F]fluoro-2-deoxy-D-glucose positron emission tomography and echocardiography after two and four DOX-doses. The cardiac histology, oxidative stress, maximal metabolic enzyme activities, and mitochondrial respiration were analyzed. RESULTS: DOX increased LV glucose uptake (LVGU) and mitochondrial uncoupling and decreased running activity, LV-weight, and ejection fraction (EF). In DOX-treated group ET blunted the increase in LVGU, increased LV-weight and EF, and lowered LV lactate dehydrogenase activity. DOX-treated exercised mice did not differ from tumor-bearing group without DOX in LVGU or from the tumor-free ET-group in LV-weight or EF whereas unexercised DOX-treated group did. ET also increased LV citrate synthase activity in tumor-bearing animals. There was an inverse association between LVGU and EF and LV-weight.CONCLUSION: In a murine breast cancer model, voluntary ET moderated DOX-induced cardiotoxicities such as increased LVGU, LV-atrophy and decreased EF. This suggests that ET might benefit patients with cancer undergoing doxorubicin treatment by mitigating cardiotoxicity.

KW - Animals

KW - Doxorubicin/adverse effects

KW - Female

KW - Physical Conditioning, Animal

KW - Breast Neoplasms/pathology

KW - Oxidative Stress/drug effects

KW - Mice

KW - Glucose/metabolism

KW - Cell Line, Tumor

KW - Heart Ventricles/drug effects

KW - Positron-Emission Tomography

U2 - 10.1186/s12967-025-06108-y

DO - 10.1186/s12967-025-06108-y

M3 - Article

C2 - 39838445

SN - 1479-5876

VL - 23

JO - Journal of Translational Medicine

JF - Journal of Translational Medicine

IS - 1

M1 - 89

ER -

Exercise training partly ameliorates cardiac dysfunction in mice during doxorubicin treatment of breast cancer

Abstract

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