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Aerobic Exercise During Early Murine Doxorubicin Exposure Mitigates Cardiac Toxicity.

ABSTRACT: We report the cardioprotective effects of moderate aerobic exercise from parallel pediatric murine models of doxorubicin (Doxo) exposure in non-tumor-bearing immune competent (NTB-IC) mice and tumor-bearing nude mice (TB-NM). In both models, animals at 4 weeks of age underwent Doxo treatment with or without 2 weeks of simultaneous exercise. In sedentary NTB-IC or TB-NM mice, Doxo treatment resulted in a statistically significant decrease in ejection fraction and fractional shortening compared with control animals. Interestingly, moderate aerobic exercise during Doxo treatment significantly mitigated decreases in ejection fraction and fractional shortening. In contrast, these protective effects of exercise were not observed when exercise was started after completion of Doxo treatments. Moreover, in the TB-NM model, Doxo caused a decrease in heart mass: tibia length and in body weight that was prevented by exercise, whereas NTB-IC mice exhibited no change in these measurements. Doxo delivery to the hearts of TB-NM was decreased by consistent moderate aerobic exercise before Doxo injection. These findings demonstrate the important but subtle differences in cardiotoxicity observed in different mouse models. Collectively, these results also strongly suggest that aerobic exercise during early-life Doxo exposure mitigates cardiotoxicity, possibly through altered delivery of Doxo to myocardial tissue.

SUBMITTER: Wang F

PROVIDER: S-EPMC6876617 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Aerobic Exercise During Early Murine Doxorubicin Exposure Mitigates Cardiac Toxicity.

Wang Fei F Iskra Brian B Kleinerman Eugenie E Alvarez-Florez Claudia C Andrews Thomas T Shaw Angela A Chandra Joya J Schadler Keri K Aune Gregory J GJ

Journal of pediatric hematology/oncology 20180401 3

We report the cardioprotective effects of moderate aerobic exercise from parallel pediatric murine models of doxorubicin (Doxo) exposure in non-tumor-bearing immune competent (NTB-IC) mice and tumor-bearing nude mice (TB-NM). In both models, animals at 4 weeks of age underwent Doxo treatment with or without 2 weeks of simultaneous exercise. In sedentary NTB-IC or TB-NM mice, Doxo treatment resulted in a statistically significant decrease in ejection fraction and fractional shortening compared wi ...[more]

PMID: 29557918

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Project description:ObjectiveTo evaluate the safety and feasibility of performing treadmill aerobic exercise in moderate normobaric hypoxia among chronic hemiparetic stroke survivors.DesignObservational study using convenience sampling.SettingResearch laboratory in a tertiary rehabilitation hospital.ParticipantsChronic hemiparetic stroke survivors who could walk at least 10-m with or without assistance and had no absolute contraindications to exercise testing.InterventionParticipants (three male and four female) were asked to complete three normobaric hypoxia exposure protocols within a single session. First, they were passively exposed to normobaric hypoxia through gradual reductions in the fraction of inspired oxygen (FIO2 = 20.9, 17.0, and 15.0%) while seated (5-min at each level of FIO2). Participants were then exposed to the same reductions in FIO2 during constant-load exercise performed on a treadmill at 40% of heart rate reserve. Finally, participants completed 20-min of exercise while intermittently exposed to moderate normobaric hypoxia (5 × 2-min at FIO2 = 15.0%) interspaced with 2-min normoxia intervals (FIO2 = 20.9%).Outcome measuresThe primary outcome was occurrence of adverse events, which included standardized criteria for terminating exercise testing, blood oxygen saturation (SpO2) <80%, or acute mountain sickness score >2. The increased cardiovascular strain imposed by normobaric hypoxia exposure at rest and during exercise was evaluated by changes in SpO2, heart rate (HR), blood pressure, and rating of perceived exertion (RPE).ResultsOne participant reported mild symptoms of nausea during exercise in normobaric hypoxia and discontinued participation. No other adverse events were recorded. Intermittent normobaric hypoxia exposure was associated with reduced SpO2 (MD = -7.4%, CI: -9.8 to -5.0) and increased HR (MD = 8.2, CI: 4.6 to 11.7) compared to intervals while breathing typical room air throughout the 20-min constant-load exercise period. The increase in HR was associated with a 10% increase in relative effort. However, reducing FIO2 had little effect on blood pressure and RPE measurements.ConclusionModerate normobaric hypoxia appeared to be a safe and feasible method to increase the cardiovascular strain of submaximal exercise in chronic hemiparetic stroke survivors. Future studies evaluating the effects of pairing normobaric hypoxia exposure with existing therapies on secondary prevention and functional recovery are warranted.

Project description:Childhood cancer survivors (CCSs) face lifelong side effects related to their treatment with chemotherapy. Anthracycline agents, such as doxorubicin (DOX), are important in the treatment of childhood cancers but are associated with cardiotoxicity. Cardiac toxicities represent a significant source of chronic disability that cancer survivors face; despite this, the chronic cardiotoxicity phenotype and how it relates to acute toxicity remains poorly defined. To address this critical knowledge gap, we studied the acute effect of DOX on murine cardiac nonmyocytes in vivo. Determination of the acute cellular effects of DOX on nonmyocytes, a cell pool with finite replicative capacity, provides a basis for understanding the pathogenesis of the chronic heart disease that CCSs face. To investigate the acute cellular effects of DOX, we present single-cell RNA sequencing (scRNAseq) data from homeostatic cardiac nonmyocytes and compare it with preexisting datasets, as well as a novel CyTOF datasets. SCANPY, a python-based single-cell analysis, was used to assess the heterogeneity of cells detected in scRNAseq and CyTOF. To further assist in CyTOF data annotation, joint analyses of scRNAseq and CyTOF data using an artificial neural network known as sparse autoencoder for clustering, imputation, and embedding (SAUCIE) are performed. Lastly, the panel is tested on a mouse model of acute DOX exposure at two time points (24 and 72 h) after the last dose of doxorubicin and examined with joint clustering. In sum, we report the first ever CyTOF study of cardiac nonmyocytes and characterize the effect of acute DOX exposure with scRNAseq and CyTOF.NEW & NOTEWORTHY We describe the first mass cytometry studies of murine cardiac nonmyocytes. The mass cytometry panel is compared with single-cell RNA sequencing data. Homeostatic cardiac nonmyocytes are characterized by mass cytometry to identify and quantify four major cell populations: endothelial cells, fibroblasts, leukocytes, and pericytes. The single-cell acute nonmyocyte response to doxorubicin is studied at 24 and 72 h after doxorubicin exposure given daily for 5 days at a dose of 4 mg/kg/day.

Dataset Information

Aerobic Exercise During Early Murine Doxorubicin Exposure Mitigates Cardiac Toxicity.

Publications

Aerobic Exercise During Early Murine Doxorubicin Exposure Mitigates Cardiac Toxicity.

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