Publications by authors named "Reid Hayward"

55 Publications

Exercise training-induced adaptations in lung cancer patients who have undergone a lobectomy.

Exp Gerontol 2021 Oct 9;155:111587. Epub 2021 Oct 9.

School of Sport and Exercise Science, University of Northern Colorado, Greeley, CO, USA; University of Northern Colorado Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO, USA. Electronic address:

Purpose: To determine the safety and effectiveness of a prescribed, individualized, 12-week exercise intervention on cardiorespiratory function, muscular strength, and quality of life in lung cancer patients who have undergone a lobectomy. In addition, we sought to compare the exercise training response of lung cancer patients who have undergone a lobectomy to a population of cancer patients with all other cancers in order to examine the specific effects of a lobectomy when compared to cancer patients at large.

Methods: Participants were referred by a physician, and upon entry, completed an exercise-based assessment and surveys to assess various quality of life measures. Participants were divided into two groups: lung cancer patients having undergone a lobectomy (LOB, n = 9) or those diagnosed with all other cancers (AOC, n = 201). Participants underwent 12 weeks of supervised exercise based on an individualized exercise prescription. Measures of cardiorespiratory function, muscular strength, and quality of life were collected prior to the intervention and after 12 weeks of exercise training.

Results: Significant improvements to VO (p < 0.05) were seen in both groups. Significant improvements to muscular strength (p < 0.05) were seen in both groups for all measures aside from shoulder press in the LOB group. Both groups showed significant improvements to aspects of fatigue and quality of life (p < 0.05), but only the AOC group significantly improved in measures of depression (p < 0.05).

Conclusion: Exercise-based rehabilitation is a safe and effective intervention for lung cancer survivors who have undergone a lobectomy. These individuals saw significant improvements in cardiorespiratory fitness, muscular strength, and quality of life. Although there were similarities in the pattern of these training-induced improvements for these groups, lung cancer patients undergoing a lobectomy consistently demonstrated lower absolute values when compared to patients with all other cancer diagnoses.
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http://dx.doi.org/10.1016/j.exger.2021.111587DOI Listing
October 2021

Kefir Is a Viable Exercise Recovery Beverage for Cancer Survivors Enrolled in a Structured Exercise Program.

Med Sci Sports Exerc 2021 Oct;53(10):2045-2053

School of Sport and Exercise Science, University of Northern Colorado, Greeley, CO.

Purpose: This study investigated the effects of 12 wk of postexercise kefir consumption in cancer survivors who have undergone chemotherapy and/or radiation therapy.

Methods: All participants were enrolled in a structured exercise training program and separated into kefir (KEF) or control (CON) treatment groups. KEF consumed 8 oz. of kefir after exercise sessions (3 d·wk-1) for 12 wk. Outcome measures included assessments for body size and composition, aerobic fitness and muscular strength, medical history, and psychological state at pre- and postintervention time points. Blood was collected and analyzed for C-reactive protein (CRP), interleukin 6 (IL-6), and lipopolysaccharide (LPS) concentrations, and LPS-stimulated whole blood IL-6 and tumor necrosis factor α production were obtained using enzyme-linked immunosorbent assays at both time points. Monocyte numbers and phenotype were obtained using flow cytometry.

Results: Participants (N = 24; 9 males and 15 females) were an average of 61 ± 9.9 yr old. Kefir consumption was associated with 6.3% (P = 0.034) improvements in lean body mass, as well as 51.4% (P = 0.046), 39.3% (P = 0.017), and 64.7% (P = 0.021) improvements in measures of depression, fatigue, and gastric distress, respectively. KEF also experienced a significant 35.4% (P = 0.01) reduction in circulating LPS along with an 18.0% increase (P < 0.001) in classical monocytes % and a 22.3% decrease (P = 0.04) in nonclassical monocytes %. There were no significant changes in any other variables.

Conclusion: Twelve weeks of kefir consumption improved lean body mass, depression, fatigue, gastric distress, and a biomarker of gut dysbiosis. Kefir improved overall and classical monocyte numbers. Kefir should be considered as a component of a postexercise dietary regimen for cancer survivors.
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http://dx.doi.org/10.1249/MSS.0000000000002690DOI Listing
October 2021

Structured Exercise in Cancer Survivors: Is it Enough for Neural, Mental Health and Well-being?

Int J Exerc Sci 2021 1;14(3):162-176. Epub 2021 Apr 1.

School of Sport and Exercise Science, University of Northern Colorado, Greeley, CO, USA.

The purpose of this cross-sectional study was to explore physical activity, depression, fatigue, and quality of life (QOL), and their relationship to brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in cancer survivors enrolled in a structured exercise program. Participants were recruited into two groups: in-treatment (IT), currently receiving chemotherapy and/or radiotherapy, and out of treatment (OT), not undergoing therapy. Participants wore accelerometers for 7 days and completed cardiorespiratory fitness, muscular strength, and depression, fatigue, and QOL assessments. Circulating BDNF and NGF concentrations were obtained using enzyme-linked immunosorbent assays. Thirty-two participants (IT: = 13, OT: = 19) with an average age of 63 years and BMI of 27.5, spent 78% of their waking hours engaged in sedentary behavior outside of exercise training. Significant correlations were observed between light physical activity (LPA) outside of exercise training and QOL in IT ( = 0.626, 0.030), and fatigue in OT ( = 0.553, 0.021). Moderate to vigorous physical activity (MVPA) outside of exercise training significantly correlated with leg press strength ( = 0.700, 0.008) in IT, and cardiorespiratory fitness ( = 0.440, 0.013) when groups were combined. Concentrations of NGF did not differ between groups, and in IT, BDNF was positively related to LPA outside of training and was significantly lower (87 ± 28.5 pg/mL) than in OT (137 ± 54 pg/mL; 0.010). While structured exercise programs should focus on improving cardiorespiratory fitness and muscular strength during exercise training, these programs should consider physical activity outside of training, if well-tolerated, to potentially further lower fatigue and improve QOL in cancer survivors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136549PMC
April 2021

Exercise training improves postural steadiness in cancer survivors undergoing chemotherapy.

Gait Posture 2021 06 20;87:136-142. Epub 2021 Apr 20.

School of Sport and Exercise Science, University of Northern Colorado, Campus Box 39, Greeley, CO, 80639, USA. Electronic address:

Background: Cancer and cancer treatments negatively affect somatosensory, vestibular, and visual inputs that regulate postural stability and balance, increasing the risk of falling. Exercise training has been shown to mitigate other negative side effects of cancer treatments, such as reducing peripheral neuropathy.

Research Question: How does 12 weeks of supervised exercise training influence postural stability in cancer survivors who receive chemotherapy?

Methods: Postural stability of cancer survivors (n = 25; mass = 79.0 ± 22.6 kg; height = 1.66 ± 0.08 m; age = 61 ± 10 years) receiving chemotherapy was assessed prior to and following a 12-week individualized exercise training program by quantifying changes in center of pressure data. A series of 2-factor (pre/post x condition) analysis of variance with repeated measures were used to identify differences between conditions and pre- and post- training program on time and frequency domain measures.

Results: Mediolateral root mean square excursion (p = 0.040; es = 0.20) and resultant mean frequency (p = 0.044; es = 0.29) of the center of pressure trajectory were found to be significantly different between pre- and post-training program. Further, participants dealt better with perturbations after completing the training program by reducing mediolateral root mean square excursion and 95 % confidence ellipse when visual stimulus was removed.

Significance: Supervised exercise training in cancer patients undergoing chemotherapy improves postural stability in the mediolateral direction. Given that mediolateral movement of the center of pressure has previously been associated with fallers in other populations, exercise training during cancer treatments may be beneficial.
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http://dx.doi.org/10.1016/j.gaitpost.2021.04.013DOI Listing
June 2021

Effects of Aerobic and Flexibility Training on Physiological and Psychosocial Function in a Patient with Anaplastic Oligodendroglioma: A Case Report.

J Rehabil Med Clin Commun 2020 4;3:1000032. Epub 2020 May 4.

School of Sport and Exercise Science, University of Northern Colorado, Denver, CO, USA.

Objective: Diagnoses of anaplastic oligodendrogliomas are rare. For cancer rehabilitation practitioners, anaplastic oligodendroglioma may impact on the development and maintenance of prescriptive exercise. Exercise interventions for healthy individuals and cancer patients have been shown to increase functional capacity, psychosocial functioning, and aspects of cognitive function. However, there is a lack of research into exercise interventions among patients with anaplastic oligodendroglioma. This case report of a patient with anaplastic oligodendroglioma, measures the effects of aerobic and flexibility training on physiological, psychosocial, and cognitive functioning.

Patient: A 44-year old woman diagnosed with class III anaplastic oligodendroglioma with 1p19q genetic co-deletion underwent left-frontal craniotomy, chemotherapy, and radiation treatment. Comprehensive physical, psychosocial, and cognitive assessments were completed before and after a 36-session exercise intervention.

Results: Following the intervention improvements were observed in 9 of the 14 physiological measures. Fatigue decreased by 20% and quality of life increased by almost 70%. Improvements were also observed in 6 of the 12 cognitive assessment variables.

Conclusion: The 36 sessions of aerobic and flexibility training were well-tolerated by the subject. The results demonstrate the feasibility and importance of aerobic and flexibility training for the attenuation of cancer-related decrements in physiological and psychosocial variables in patients with anaplastic oligodendroglioma. The effects on cognitive function were uncertain.
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http://dx.doi.org/10.2340/20030711-1000032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008718PMC
May 2020

Physical activity delays accumulation of immunosuppressive myeloid-derived suppressor cells.

PLoS One 2020 15;15(6):e0234548. Epub 2020 Jun 15.

School of Sport and Exercise Science and the University of Northern Colorado Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO, United States of America.

Background: Myeloid-derived suppressor cells (MDSCs) are potent suppressors of immune function and may play a key role in the development and progression of metastatic cancers. Aerobic exercise has been shown to have anticancer effects, yet the mechanisms behind this protection are largely unknown. Therefore, we examined the effects of physical activity on MDSC accumulation and function.

Methods: Female BALB/c mice were assigned to one of two primary groups: sedentary tumor (SED+TUM) or wheel run tumor (WR+TUM). After 6 weeks of voluntary wheel running, all animals were randomly subdivided into 4 different timepoint groups; 16, 20, 24, and 28 days post-tumor injection. All mice were inoculated with 4T1 mammary carcinoma cells in the mammary fat pad and WR groups continued to run for the specified time post-injection. Spleen, blood, and tumor samples were analyzed using flow cytometry to assess proportions of MDSCs.

Results: Cells expressing MDSC biomarkers were detected in the spleen, blood, and tumor beginning at d16. However, since there was no evidence of immunosuppressive function until d28, we refer to them as immature myeloid cells (IMCs). Compared to SED+TUM, levels of IMCs in the spleen were significantly lower (p < 0.05) in WR+TUM at day 16 (33.0 ± 5.2%; 23.1 ± 10.2% of total cells, respectively) and day 20 (33.9 ± 8.1%; 24.3 ± 5.1% of total cells, respectively). Additionally, there were fewer circulating IMCs in WR+TUM at day 16 and MDSC levels were significantly lower (p < 0.05) in the tumor at day 28 in WR+TUM. Additionally, a non-significant 62% and 26% reduction in metastatic lung nodules was observed at days 24 and 28, respectively. At day 28, MDSCs harvested from SED+TUM significantly suppressed CD3+CD4+ T cell proliferation (3.2 ± 1.3 proliferation index) while proliferation in WR+TUM MDSC co-cultures (5.1 ± 1.7 proliferation index) was not different from controls.

Conclusions: These findings suggest that physical activity may delay the accumulation of immunosuppressive MDSCs providing a broader window of opportunity for interventions with immunotherapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234548PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295224PMC
August 2020

Effects of Calorie Restriction and Voluntary Exercise on Doxorubicin-Induced Cardiotoxicity.

Integr Cancer Ther 2019 Jan-Dec;18:1534735419843999

3 University of Northern Colorado, Greeley, CO, USA.

Introduction: Doxorubicin (DOX) is a widely used chemotherapeutic agent with known cardiotoxic properties, while calorie restriction (CR) and exercise have well-documented cardioprotective effects. No studies have investigated the effects of CR alone or the combined effects of CR and exercise on DOX cardiotoxicity.

Methods: Rats were divided into 4 groups based on their food intake (ad libitum or CR) and activity (sedentary or voluntary wheel running [WR]). After completing a 16-week treatment, animals received either DOX (15 mg/kg) or saline (SAL) and cardiac function was measured 5 days after treatment. Chromatography was used to quantify left ventricular DOX accumulation.

Results: Left ventricular developed pressure (LVDP), end systolic pressure (ESP), and left ventricular maximal rate of pressure development (dP/dt) were significantly higher in the CR + DOX group when compared with DOX. Fractional shortening, LVDP, ESP, dP/dt, and dP/dt were significantly higher in the CR + WR + DOX group compared with the DOX group. In addition, the CR + WR + DOX group showed significantly higher LVDP and ESP compared with the WR + DOX group. DOX accumulation in the heart was 5-fold lower ( P < .05) in the CR + WR + DOX group compared with the DOX group.

Conclusion: This is the first study to demonstrate that CR can reduce cardiac DOX accumulation, and confirms the protective role of CR against DOX-induced cardiac dysfunction. Our data also show that combining a known cardioprotective intervention, exercise training, with CR results in additive benefits in the protection against DOX cardiotoxicity.
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http://dx.doi.org/10.1177/1534735419843999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475835PMC
December 2019

Cardiorespiratory fitness, visceral fat, and body fat, but not dietary inflammatory index, are related to C-reactive protein in cancer survivors.

Nutr Health 2019 Sep 16;25(3):195-202. Epub 2019 Apr 16.

School of Sport and Exercise Science, University of Northern Colorado, Greeley, CO, USA.

Background: The control of chronic inflammation has emerged as a target for improving the health of cancer survivors (CS).

Aim: To examine differences in fitness and dietary characteristics of CS when grouped by low vs. moderate to high serum C-reactive protein (CRP).

Methods: CS ( = 26, mean age = 68 ± 12 years) were evaluated for body mass index (BMI), body composition, cardiorespiratory fitness, dietary intake, dietary inflammatory index (DII), and serum CRP. Participants were assigned to one of two groups based on serum CRP concentrations: low CRP (≤1 mg/L) (LWC; = 13) or moderate to high (CRP > 1 mg/L) (MHC; = 13) and t-tests compared them. Data are presented as mean ± SD.

Results: LWC had higher VOpeak values (mL/kg/min) ( = 0.0003), and lower visceral fat area (cm) ( = 0.02) and body fat mass (kg) ( = 0.04). Secondary analysis using Pearson's correlation coefficients, including all current study participant data, found significant negative relationships between CRP and total dietary fat intake ( = 0.02), saturated fat ( = 0.03), and polyunsaturated fat ( = 0.03).

Conclusion: CS with moderate to high serum CRP concentrations had higher fat mass, visceral fat mass, and lower cardiorespiratory fitness. There was a significant negative relationship between dietary, fat, polyunsaturated and saturated fat, and CRP. However, these dietary fat related findings warrant further investigation. To summarize, improving cardiorespiratory fitness, maintaining lower body fat, may be helpful in altering chronic inflammation in CS.
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http://dx.doi.org/10.1177/0260106019841840DOI Listing
September 2019

Validation of the 6-min Walk Test for Predicting Peak V˙O2 in Cancer Survivors.

Med Sci Sports Exerc 2019 02;51(2):271-277

School of Sport and Exercise Science, and the University of Northern Colorado Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO.

Purpose: To assess the quality of the relationship between V˙O2peak estimated from patient outcomes on the 6-min walk test (6MWT) and the V˙O2peak calculated from patient outcomes on the University of Northern Colorado Cancer Rehabilitation Institute (UNCCRI) treadmill protocol.

Methods: Cancer survivors (N = 187) completed the UNCCRI treadmill protocol and a 6MWT 1 wk apart in randomized order to obtain V˙O2peak. Values from the UNCCRI treadmill protocol were compared against four common 6MWT V˙O2peak prediction equations.

Results: All four 6MWT prediction equations significantly (P < 0.001) underestimated V˙O2peak with predicted values ranging from 8.0 ± 4.1 mL·kg·min to 18.6 ± 3.1 mL·kg·min, whereas the UNCCRI treadmill protocol yielded a significantly higher value of 23.9 ± 7.6 mL·kg·min. A positive strong correlation occurred between estimated V˙O2peak derived from the UNCCRI treadmill protocol and only one of the V˙O2peak values derived from the 6MWT prediction equations (r = 0.81), and all four equations consistently underpredicted V˙O2peak.

Conclusions: These findings suggest that the 6MWT is not a valid test for predicting V˙O2peak in the cancer population due to its consistent underestimation of V˙O2peak regardless of the prediction equation. Obtaining an accurate and valid V˙O2peak value is necessary to correctly prescribe an individualized exercise rehabilitation regimen for cancer survivors. It is recommended that clinicians avoid the 6MWT and instead implement treadmill testing to volitional fatigue to quantify V˙O2peak in cancer survivors.
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http://dx.doi.org/10.1249/MSS.0000000000001790DOI Listing
February 2019

Effects of an Exercise Intervention on Cancer-Related Fatigue and Its Relationship to Markers of Oxidative Stress.

Integr Cancer Ther 2018 06 12;17(2):503-510. Epub 2018 Apr 12.

2 Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO, USA.

Background: Although the underlying mechanisms of cancer-related fatigue (CRF) are not fully characterized, treatment-associated oxidative stress may play a role. The purpose of this study was to determine the effect of an exercise intervention on the relationship between CRF and oxidative stress.

Methods: Upon cessation of radiation or chemotherapy, 8 cancer patients participated in a 10-week exercise intervention (EX), while 7 continued standard care (CON). Blood draws and fatigue questionnaires were administered to cancer patients before and after the intervention as well as to 7 age-matched individuals with no cancer history. Changes in plasma 8-hydroxy-deoxyguanosine (8-OHdG), protein carbonyls, antioxidant capacity, and fatigue were compared between groups. Correlations between CRF and oxidative stress were evaluated.

Results: Mean total fatigue scores decreased significantly (5.0 ± 2.2 to 2.6 ± 1.5, P < .05) in EX, but not in CON. Antioxidant capacity significantly increased (+41%; P < .05) and protein carbonyls significantly decreased (-36%; P < .05) in EX, but not in CON. Increases in antioxidant capacity were significantly correlated with reductions in affective ( r = -.49), sensory ( r = -.47), and cognitive fatigue ( r = -.58). Changes in total ( r = .46) and affective ( r = .47) fatigue exhibited significant correlations with changes in 8-OHdG over time, while behavioral ( r = .46) and sensory ( r = .47) fatigue changes were significantly correlated with protein carbonyls.

Conclusions: Oxidative stress may be implicated in CRF, while improved antioxidant capacity following an exercise intervention may play a role in mitigating CRF in cancer survivors.
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http://dx.doi.org/10.1177/1534735418766402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041925PMC
June 2018

Effects of Resistance Exercise Training on Doxorubicin-Induced Cardiotoxicity.

J Cardiovasc Pharmacol 2018 06;71(6):332-339

School of Sport and Exercise Science, University of Northern Colorado Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO.

Although highly effective, doxorubicin (DOX) use is limited by a dose-dependent cardiotoxicity. The purpose of this study was to determine whether resistance training (RT) would protect against DOX-induced cardiac dysfunction and determine whether any observed functional preservation is a result of reduced lipid peroxidation or a preservation of the cardiac myosin heavy chain (MHC) isoform distribution. Rats were resistance-trained or remained sedentary for 12 weeks, then treated with 12.5 mg/kg DOX or 0.9% saline. Five days after DOX exposure, cardiac function, lipid peroxidation, and MHC isoform expression were quantified. RT preserved cardiac function and attenuated the α-to β-MHC shift that occurs with DOX treatment. No significant differences in lipid peroxidation were observed between sedentary and RT animals treated with DOX. These data suggest that resistance-type exercise can provide protection against DOX-induced cardiac dysfunction, which may be a result of a preservation of the cardiac MHC isoform distribution.
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http://dx.doi.org/10.1097/FJC.0000000000000574DOI Listing
June 2018

Feasibility of a combined aerobic and cognitive training intervention on cognitive function in cancer survivors: a pilot investigation.

Pilot Feasibility Stud 2018 17;4:50. Epub 2018 Feb 17.

3School of Sport and Exercise Science, University of Northern Colorado Cancer Rehabilitation Institute, University of Northern Colorado, 501 W. 20th St., Greeley, CO 80639 USA.

Background: Cancer-related cognitive impairment (CRCI) may negatively affect upwards of 75% of cancer patients. Exercise and cognitive training, independently, may increase functional capacity and aspects of cognitive function. Yet, combined training protocols have not been evaluated in cancer survivor populations. Therefore, the aim of this study was to explore the feasibility of a quasi-randomized, controlled, exploratory, repeated-measures aerobic and cognitive training intervention on cognitive function in participants undergoing treatment for cancer ( = 28).

Methods: Pre- and post-physical and cognitive assessments were administered. A 36-session (approximately 12 weeks) computer-based cognitive (COG), aerobic (AER), cognitive and aerobic (AER + COG), and flexibility (CON) training intervention was completed. Dependent measures tests and pre- to post percentages were then calculated to address within-group changes for each dependent variable.

Results: Within-group measures revealed that the AER logical memory scores (pre- to post mean difference [2.3], 95.0% CI [0.9, 3.7], percentage change [32.7%]), delayed recall scores (pre- to post mean difference [2.1], 95.0% CI [0.3, 3.9], percentage change [27.2%]), block design scores (pre- to post mean difference [1.7], 95.0% CI [0.2, 3.2], percentage change [19.0%]), and letter-number sequencing scores (pre- to post mean difference [1.0], 95.0% CI [0.2, 1.8], percentage change [12.3%]) all increased. Aspects of verbal fluidity scores increased in the CON group. However, all cognitive scores (AER + COG and COG groups) failed to increase.

Conclusions: Aerobic training for CRCI may positively impact cognitive function. Individually, these methods may appropriately address CRCI, but combined training of this nature may be too demanding for patients undergoing treatment for cancer. However, larger randomized trials are needed to substantiate this protocol in large-scale cancer rehabilitation centers.
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http://dx.doi.org/10.1186/s40814-018-0242-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816373PMC
February 2018

Exercise Protects against Cancer-induced Cardiac Cachexia.

Med Sci Sports Exerc 2018 06;50(6):1169-1176

School of Sport and Exercise Science, and the University of Northern Colorado Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO.

Cancer has been shown to negatively stimulate autophagy, leading to a decline in cardiac function. Although exercise is cardioprotective, its influence over autophagy-mediated tumor growth and cardiac function are not well defined.

Purpose: This study aimed to determine the effect of exercise on tumor morphology and cardiac function.

Methods: Fisher 344 rats (n = 28) were assigned to one of four groups: 1) sedentary non-tumor bearing (SED), 2) sedentary tumor bearing (SED + T), 3) wheel run non-tumor bearing (WR), or 4) wheel run tumor bearing (WR + T). Rats remained sedentary or exercised for 6 wk. At week 4, rats in tumor groups were inoculated with MatBIII tumor cells. At week 6, cardiac function was measured.

Results: SED + T animals exhibited significantly lower left ventricular developed pressure when compared with SED, WR, and WR + T (P < 0.05). This coincided with a significant increase in cardiac autophagy (increased LC3-II) in SED + T animals when compared with SED, WR, and WR + T (P < 0.05). Furthermore, SED + T hearts showed a significant increase in β-myosin heavy chain expression versus nontumor groups (P < 0.05). Tumor mass was significantly larger (P < 0.001) in SED + T animals when compared with WR + T animals, which was accompanied by a significant increase in tumor LC3-II protein expression (P < 0.05).

Conclusion: Nonexercised tumor-bearing rats showed severe cardiac dysfunction and excessive, maladaptive autophagy in the heart and tumors. Voluntary exercise preserved cardiac function and attenuated the autophagic response in heart and tumor tissues. This preservation may be related to the reduced tumor growth in aerobically exercised rats, to the improved regulation of autophagy by exercise, or both.
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http://dx.doi.org/10.1249/MSS.0000000000001544DOI Listing
June 2018

Research priorities in cancer cachexia: The University of Rochester Cancer Center NCI Community Oncology Research Program Research Base Symposium on Cancer Cachexia and Sarcopenia.

Curr Opin Support Palliat Care 2017 Dec;11(4):278-286

aWilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York bDepartment of Medicine, University of Washington School of Medicine, Seattle, Washington cDepartment of Supportive Care Medicine, City of Hope, Duarte dSchool of Sport and Exercise Science, University of Northern Colorado, Greeley, Colorado eDepartment of Medicine, Brown University, Providence, Rhode Island fDepartment of Medicine, The University of Chicago, Chicago, Ilinois gKaiser Permanente Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.

Purpose Of Review: Cancer cachexia remains understudied and there are no standard treatments available despite the publication of an international consensus definition and the completion of several large phase III intervention trials in the past 6 years. In September 2015, The University of Rochester Cancer Center NCORP Research Base led a Symposium on Cancer Cachexia and Sarcopenia with goals of reviewing the state of the science, identifying knowledge gaps, and formulating research priorities in cancer cachexia through active discussion and consensus.

Recent Findings: Research priorities that emerged from the discussion included the implementation of morphometrics into clinical decision making, establishing specific diagnostic criteria for the stages of cachexia, expanding patient selection in intervention trials, identifying clinically meaningful trial endpoints, and the investigation of exercise as an intervention for cancer cachexia.

Summary: Standardizing how we define and measure cancer cachexia, targeting its complex biologic mechanisms, enrolling patients early in their disease course, and evaluating exercise, either alone or in combination, were proposed as initiatives that may ultimately result in the improved design of cancer cachexia therapeutic trials.
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http://dx.doi.org/10.1097/SPC.0000000000000301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658778PMC
December 2017

Marijuana use and inpatient outcomes among hospitalized patients: analysis of the nationwide inpatient sample database.

Cancer Med 2017 01 28;6(1):320-329. Epub 2016 Nov 28.

University of Northern Colorado Cancer Rehabilitation Institute, Greeley, Colorado.

The purpose of this paper is to examine the relationship between marijuana use and health outcomes among hospitalized patients, including those hospitalized with a diagnosis of cancer. A total of 387,608 current marijuana users were identified based on ICD-9 codes for marijuana use among hospitalized patients in the Nationwide Inpatient Sample database between 2007 and 2011. Logistic regression analysis was performed to determine the association between marijuana use and heart failure, cardiac disease, stroke, and in-hospital mortality. All models were adjusted for age, gender, race, residential income, insurance, residential region, pain, and number of comorbidities. Among hospitalized patients, marijuana use was associated with a 60% increased odds of stroke (OR: 1.60, 95% CI: 1.44-1.77) compared with non-users, but significantly reduced odds of heart failure (OR: 0.78, 95% CI: 0.75-0.82), cardiac disease (OR: 0.86, 95% CI: 0.82-0.91), or in-hospital mortality (OR: 0.41, 95% CI: 0.38-0.44). Among cancer patients, odds of in-hospital mortality was significantly reduced among marijuana users compared with non-users (OR: 0.44, 95% CI: 0.35-0.55). Hospitalized marijuana users were more likely to experience a stroke compared with non-users, but less likely to experience in-hospital mortality. Prospective studies will be needed to better characterize the health effects of marijuana use, especially among older, sicker, and/or hospitalized patients. In the meantime, conversations regarding marijuana use/misuse may be warranted in the clinical setting in order for patients and healthcare providers to adequately weigh the anticipated benefits of marijuana use with potentially significant health risks.
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http://dx.doi.org/10.1002/cam4.968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5269570PMC
January 2017

Effects of Exercise on Doxorubicin-Induced Skeletal Muscle Dysfunction.

Med Sci Sports Exerc 2016 08;48(8):1468-73

1School of Sport and Exercise Science, University of Northern Colorado, Greeley, CO; and 2The University of Northern Colorado Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO.

Introduction: Chemotherapy treatment with doxorubicin (DOX) can have a negative effect on normal skeletal muscle function. Recent research demonstrates the potential value of exercise in alleviating DOX-induced cardiotoxicity. Yet up to now, little research has been done to examine whether exercise might also be effective in addressing DOX's skeletal muscle adverse effects, especially because posttreatment skeletal muscle dysfunction may cause patient difficulties with completing activities of daily living. The main aim of this study was to examine how resistance training (RT) and treadmill (TM) training play a role in preventing DOX-induced skeletal muscle dysfunction.

Methods: Male Sprague-Dawley rats were randomly placed into an RT, TM, or sedentary (SED) group for 10 wk and then received either a bolus injection of DOX (15 mg·kg) or saline as a control. Skeletal muscle function was then assessed ex vivo 5 d after injection.

Results: SED animals treated with DOX showed significantly lower maximal twitch force, maximal rate of force production, and maximal rate of force decline versus SED + saline in the soleus (SOL) (Type I muscle). In the extensor digitorum longus (Type II muscle), treatment with DOX resulted in a significantly lower maximal rate of force production and maximal rate of force decline. RT preserved maximal twitch force and maximal rate of force decline in the SOL. TM attenuated DOX-induced fatigue in the SOL but not in the extensor digitorum longus.

Conclusion: These findings suggest that RT and TM before DOX could be useful in preserving skeletal muscle function and minimizing fatigue after chemotherapy, but this protection may be dependent on the skeletal muscle type.
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http://dx.doi.org/10.1249/MSS.0000000000000926DOI Listing
August 2016

Effects of Chronic Endurance Exercise on Doxorubicin-Induced Thymic Damage.

Integr Cancer Ther 2016 12 20;15(4):535-541. Epub 2015 Nov 20.

University of Northern Colorado, Greeley, CO, USA

The use of prior exercise training has shown promise in minimizing doxorubicin (DOX)-induced physical impairments. The purpose of this study was to compare changes in thymus mass, thymocyte (T-cell) number, and tissue peroxidation following chronic endurance exercise and DOX treatment in the rat. The thymus mass, number of viable T-cells, and levels of malondialdehyde and 4-hydroxyalkenals (MDA+4-HAE) were compared 3 days post-injection between rats assigned to the following treatment conditions: (a) 10 weeks of endurance training, followed by a saline injection 24 hours after the last training session (TM+SAL); (b) treadmill training as above, followed by a single, bolus 10-mg/kg injection of DOX (TM+10); (c) treadmill training with 12.5 mg/kg of DOX (TM+12.5); (d) sedentary (without exercise) and a saline injection (SED+SAL); (e) sedentary with 10 mg/kg of DOX (SED+10); and (f) sedentary with 12.5 mg/kg (SED+12.5). Thymic mass and T-cell numbers significantly decreased following DOX injections. TM rats exhibited significantly less lipid peroxidation compared with paired-dose SED groups. TM+10 did not significantly differ from SED+SAL in thymic levels of lipid peroxidation. We conclude that chronic endurance exercise decreases levels of lipid peroxidation in the thymus seen with acute DOX treatment.
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http://dx.doi.org/10.1177/1534735415617014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739152PMC
December 2016

Oxidative Stress and Fitness Changes in Cancer Patients after Exercise Training.

Med Sci Sports Exerc 2016 Apr;48(4):607-14

1Department of Health Sciences, Northern Arizona University, Flagstaff, AZ; 2School of Sport and Exercise Science and the Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO.

Introduction: The purpose of this study was to determine the effect of an exercise intervention (EX) on muscular strength, cardiorespiratory fitness (CRF), and oxidative stress in cancer survivors compared with a nonexercising cancer control group (CON).

Methods: Fifteen cancer patients and seven age-matched individuals with no history of cancer (NC) participated in this study. A blood draw and assessments of muscular strength and CRF were administered to cancer survivors within 6 wk of completing radiation or chemotherapy, and again 10 wk later. Eight cancer patients completed a 10-wk supervised exercise intervention, whereas seven continued standard care. Baseline oxidative stress was compared between cancer patients and the NC group. Changes in plasma protein carbonyls, 8-OHdG, and Trolox equivalent antioxidant capacity were compared between groups using repeated-measures ANOVA, and correlations between fitness and oxidative stress changes were evaluated.

Results: Baseline antioxidant capacity was significantly lower, and plasma protein carbonyls were significantly higher in cancer patients compared with NC (P = 0.001). EX had a significant increase in antioxidant capacity (P < 0.001) and decrease in protein carbonyls (P = 0.023), whereas CON did not. Improvements in composite arm (41%, P = 0.002) and leg strength (34%, P = 0.008), isometric handgrip strength (11%, P = 0.015), and V˙O2peak (16%, P = 0.018) were significant in EX but not in CON. 8-OHdG changes were significantly correlated with changes in V˙O2peak (r = -0.89, P < 0.001), arm strength (r = -0.67, P = 0.004), and leg strength (r = -0.56, P = 0.019).

Conclusion: A whole-body exercise intervention for cancer survivors may be an effective method of concurrently increasing muscular strength, CRF, and antioxidant capacity while decreasing markers of oxidative stress.
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http://dx.doi.org/10.1249/MSS.0000000000000821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979000PMC
April 2016

Short-term exercise training attenuates acute doxorubicin cardiotoxicity.

J Physiol Biochem 2015 Dec 24;71(4):669-78. Epub 2015 Sep 24.

School of Sport and Exercise Science and Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO, 80639, USA.

Doxorubicin (DOX) is a potent and widely used antineoplastic agent. Despite the efficacy of DOX, its clinical use is limited by a dose-dependent cardiotoxicity. Chronic exercise training has been shown to protect against DOX-induced cardiotoxicity. It is less clear whether short-term exercise can attenuate DOX-induced dysfunction. The purposes of this study were to determine if short-term wheel running and treadmill exercise training can attenuate the cardiac dysfunction that accompanies DOX treatment and to investigate possible mechanisms that may be involved with any protective effects of exercise. Male Sprague-Dawley rats engaged in a short-term 5-day voluntary wheel running (WR) or treadmill exercise (TM) regimen. Following the exercise preconditioning period, animals received either 10 or 15 mg/kg of DOX or an equivalent volume of saline (SAL). Five days after DOX/SAL exposure, cardiac function was examined. Western immunoblotting was used to quantify left ventricular sarcoendoplasmic reticulum calcium-ATPase 2a (SERCA2a) protein expression. Exercise preconditioning attenuated in vivo and ex vivo cardiac dysfunction observed with DOX treatment alone. Specifically, short-term treadmill exercise (TM + DOX10, 56 ± 4%; TM + DOX15, 48 ± 5%) and voluntary wheel running (WR + DOX10, 51 ± 5%; WR + DOX15, 45 ± 3%) consistently preserved fractional shortening when compared to sedentary (SED) animals treated with DOX (SED + DOX10, 48 ± 4%; SED + DOX15, 39 ± 6%). Likewise, both exercise protocols preserved left ventricular developed pressure (TM + DOX10, 115 ± 6 mmHg; TM + DOX15, 85 ± 5 mmHg; WR + DOX10, 92 ± 12 mmHg; WR + DOX15, 91 ± 8 mmHg) when compared to SED animals treated with DOX (SED + DOX10, 79 ± 6 mmHg; SED + DOX15, 69 ± 7 mmHg). SERCA2a expression was also preserved in TM + DOX and WR + DOX. These findings suggest that short-term exercise prior to DOX treatment may be a valuable adjuvant therapy to offset acute cardiotoxicities and that maintaining calcium handling in cardiomyocytes may be responsible, in part, for the preservation in cardiac function.
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http://dx.doi.org/10.1007/s13105-015-0432-xDOI Listing
December 2015

Exercise training does not affect anthracycline antitumor efficacy while attenuating cardiac dysfunction.

Am J Physiol Regul Integr Comp Physiol 2015 Sep 5;309(6):R675-83. Epub 2015 Aug 5.

School of Sport and Exercise Science, University of Northern Colorado, Greeley, Colorado; and Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, Colorado

Highly effective anthracyclines, like doxorubicin (DOX), have limited clinical use due to protracted cardiotoxic effects. While exercise is known to be cardioprotective, it is unclear whether exercise compromises chemotherapy treatment efficacy. To determine the effect of exercise training on DOX antitumor efficacy as well as DOX-induced cardiotoxicity, female Fisher 344 rats were randomly assigned to sedentary + saline (SED+SAL), SED+DOX, wheel run exercise training + SAL (WR+SAL), or WR+DOX. On week 11, animals were inoculated with 1×10(6) MatBIII tumor cells. Once tumors reached ∼1 cm in diameter, animals were treated with 12 mg/kg of DOX or SAL. Animals were killed 1, 3, or 5 days following treatment. Tumor growth and cardiac function were measured at each interval. DOX accumulation and multidrug resistance protein (MRP) expression were quantified in tumor and heart tissue. No significant difference (P > 0.05) existed between DOX-treated SED and WR groups for tumor measurements. Exercise preserved cardiac function up to 5 days following DOX treatment. Exercise reduced ventricular DOX accumulation and upregulated ventricular MPR1 and MPR2. In contrast, no differences were observed in DOX accumulation or MRP expression in tumors of SED and WR animals. Endurance exercise had no effect on DOX antitumor efficacy as evidenced by a definitive DOX-induced reduction in tumor growth in both the SED and WR groups. Although exercise did not affect the antitumor efficacy of DOX, it still provided protection against cardiac dysfunction. These effects may be mediated by the degree of DOX tissue accumulation secondary to the regulation of MRP expression.
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http://dx.doi.org/10.1152/ajpregu.00185.2015DOI Listing
September 2015

Cancer type does not affect exercise-mediated improvements in cardiorespiratory function and fatigue.

Integr Cancer Ther 2014 Nov 22;13(6):473-81. Epub 2014 Aug 22.

University of Northern Colorado and the Rocky Mountain Cancer Rehabilitation Institute, Greeley, CO, USA

Purpose: Despite mounting evidence indicating that exercise training has a positive effect on cancer recovery, the influence of cancer type on the response to exercise training remains uncharacterized. Therefore, the adaptations to exercise training were compared between groups composed of 7 different forms of cancer.

Methods: A total of 319 cancer survivors completed fatigue inventories and participated in assessments of cardiorespiratory function, which encompassed aerobic capacity (VO2 peak), pulmonary function (forced vital capacity [FVC] and forced expiratory volume in 1 second [FEV1]), and resting blood pressure and heart rate. Participants were divided into 7 groups based on cancer type, including breast cancer (BC, n = 170), prostate cancer and other male urogenital neoplasia (PC, n = 38), hematological malignancies (HM, n = 34), colorectal cancer (CC, n = 25), gynecological cancers (GC, n = 20), glandular and epithelial neoplasms (GEN, n = 20), and lung cancer (LC, n = 12). All participants completed an individualized, multimodal exercise intervention consisting of cardiorespiratory, flexibility, balance, and muscular strength training 3 days per week for 3 months. Following the intervention, all subjects were reassessed. Generalized Estimating Equations with exchangeable working correlation structure was used to model each response; the group by time interaction effect represented the effect of cancer type on exercise-associated improvements.

Results: No significant (P > .05) group by time interaction effects were observed between different types of cancer for any parameter. Pre- to postexercise contrasts revealed significant improvements in VO2 peak in BC, PC, HM, and GEN at the Bonferroni adjusted significance level (.00714). Heart rate was significantly lowered in the BC and CC groups. Mean fatigue indices decreased by at least 17% in all groups, but these changes were only significant in the BC, HM, CC, and GC groups. Systolic blood pressure decreased significantly in BC and GC, and diastolic blood pressure decreased significantly only in the BC group while pulmonary function remained unchanged in all cancer types.

Conclusion: Although trends toward improved cardiorespiratory and fatigue parameters only reached significance in some groups, there were no significant differences between cancer types. This suggests that cardiorespiratory and fatigue improvements following rehabilitative exercise are not dependent on cancer type. Further research investigating alternative physiological parameters are needed to confirm the relationship between cancer type and exercise-mediated rehabilitation.
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http://dx.doi.org/10.1177/1534735414547108DOI Listing
November 2014

Endurance exercise attenuates cardiotoxicity induced by androgen deprivation and doxorubicin.

Can J Physiol Pharmacol 2014 May 10;92(5):356-62. Epub 2014 Mar 10.

a School of Sport and Exercise Science, University of Northern Colorado, Greeley, CO 80639, USA.

Doxorubicin (DOX) is associated with cardiac dysfunction and irreversible testicular damage. Androgen deprivation therapy (ADT) is administered prior to DOX treatment to preserve testicular function. However, ADT may exacerbate DOX-induced cardiac dysfunction. Exercise is cardioprotective, but the effects of exercise on cardiac function during combined ADT and DOX treatment are currently unknown. In this study, male Sprague-Dawley rats were randomly assigned to experimental groups: control (CON), ADT, DOX, or ADT+DOX. Animals received ADT or control implants on days 1 and 29 of the 56-day protocol. Animals remained sedentary (SED) or engaged in treadmill endurance exercise (TM) beginning on day 1. On day 15, the animals received DOX at 1 mg·(kg body mass)(-1)·d(-1) by intraperitoneal injection for 10 consecutive days, or an equivalent volume of saline. On day 57, cardiac function was assessed in vivo and ex vivo. Animals treated with DOX alone, or with combined ADT+DOX, showed significant (P < 0.05) reductions in left ventricular developed pressure (-21% and -27%), maximal rate of pressure development (-29% and -32%), and maximal rate of pressure decline (25% and 31%), respectively when compared with the sedentary control animals. Endurance exercise training attenuated (P > 0.05) cardiac dysfunction associated with combined ADT+DOX treatment, indicating that exercise during simultaneous ADT+DOX treatment is cardioprotective.
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http://dx.doi.org/10.1139/cjpp-2013-0294DOI Listing
May 2014

Effects of age on multidrug resistance protein expression and doxorubicin accumulation in cardiac and skeletal muscle.

Xenobiotica 2014 May 18;44(5):472-9. Epub 2013 Oct 18.

School of Sport and Exercise Science and.

1. Doxorubicin (DOX) is a highly effective and commonly used anthracycline antibiotic used to treat cancer patients. The side effects of DOX are manifested in a more delayed manner in children and multidrug resistant proteins (MRPs) may factor into this phenomenon. MRPs are known to extrude DOX and may factor into the degree of cardiac DOX accumulation. 2. The purpose of this study was to examine age-related differences in muscle MRP expression and DOX accumulation. 3. Female Sprague-Dawley rats were randomly selected to receive a 15-mg DOX/kg body weight bolus injection (i.p.) at various ages. 4. Cardiac and extensor digitorum longus DOX accumulation was markedly increased as animals aged from 4 to 24 weeks. In contrast, no differences in soleus accumulation were observed. A significant age-related reduction in MRP-2 and MRP-7 expression was detected in cardiac and extensor digitorum longus tissues with no age differences in MRP-1 expression in any tissues analyzed. MRP-6 was not detected in any tissues. 5. These data suggest that aging is associated with increased DOX accumulation and an age-related decrease in MRP expression may be a factor.
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http://dx.doi.org/10.3109/00498254.2013.846489DOI Listing
May 2014

Doxorubicin-induced vascular dysfunction and its attenuation by exercise preconditioning.

J Cardiovasc Pharmacol 2013 Oct;62(4):355-60

School of Sport and Exercise Science and the Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO.

Doxorubicin (DOX) is a highly effective anthracycline antibiotic used to treat a wide array of cancers. Its use is limited because of dose-dependent cardiovascular toxicity. Although exercise training has been shown to protect against DOX-induced cardiotoxicity, it is unclear as to whether exercise can attenuate DOX-induced vascular dysfunction. The purpose of this study was to determine if exercise training provides protection against the deleterious vascular effects of DOX treatment and if any changes in vascular function are related to the accumulation of DOX in vascular tissue. Male Sprague-Dawley rats remained sedentary (SED) or engaged in 14 weeks of voluntary wheel running (WR). After the 14-week period, animals received 15 mg DOX per kilogram of body mass or an equivalent volume of saline. Twenty-four hours after DOX/saline exposure, the aorta was isolated and was used to examine vascular function and aortic DOX accumulation. Aortic rings from WR + DOX animals contracted with significantly greater force and showed improved endothelium-independent relaxation when compared with rings from SED + DOX animals. In contrast, no significant differences in endothelium-dependent aortic function were noted between WR + DOX and SED + DOX. Furthermore, no significant differences in aortic DOX accumulation were observed between the DOX groups. These results suggest that chronic exercise attenuates vascular smooth muscle dysfunction associated with DOX treatment and seems to be independent of DOX accumulation in vascular tissue.
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http://dx.doi.org/10.1097/FJC.0b013e31829c9993DOI Listing
October 2013

Exercise mitigates cardiac doxorubicin accumulation and preserves function in the rat.

J Cardiovasc Pharmacol 2013 Sep;62(3):263-9

*School of Sport and Exercise Science and the Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO; †Department of Exercise and Rehabilitative Sciences, Slippery Rock University, Slippery Rock, PA; and ‡Department of Athletics, National Taiwan University, Taipei, Taiwan.

Purpose: Doxorubicin (DOX) is an effective antineoplastic agent with well-characterized cardiotoxic effects. Although exercise has been shown to protect against DOX cardiotoxicity, a clear and concise mechanism to explain its cardioprotective effects is lacking. The purpose of this study was to determine if exercise training reduces cardiac DOX accumulation, thereby providing a possible mechanism to explain the cardioprotective effects of exercise against DOX toxicity.

Methods: Sprague-Dawley rats were randomly assigned to 1 of 3 primary experimental groups: sedentary (n = 77), wheel running (n = 65), or treadmill (n = 65). Animals in wheel running and treadmill groups completed 10 weeks of exercise before DOX treatment. DOX was administered 24 hours after the last training session as a bolus intraperitoneal injection at 10 mg/kg. Subgroups of rats from each primary group were killed at 1, 3, 5, 7, and 9 days after DOX exposure to assess cardiac function and DOX accumulation.

Results: Ten weeks of exercise preconditioning reduced myocardial DOX accumulation, and this reduction in accumulation was associated with preserved cardiac function.

Conclusions: These data suggest that the cardioprotective effects of exercise against DOX-induced injury may be due, in part, to a reduction in myocardial DOX accumulation.
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http://dx.doi.org/10.1097/FJC.0b013e3182982ce0DOI Listing
September 2013

Switching to a low-fat diet attenuates the intensified doxorubicin cardiotoxicity associated with high-fat feeding.

Cancer Chemother Pharmacol 2013 Jun 9;71(6):1551-60. Epub 2013 Apr 9.

School of Sport and Exercise Science, University of Northern Colorado, Greeley, CO 80639, USA.

Purpose: A high-fat diet has been shown to exacerbate the cardiotoxicity associated with the chemotherapy drug doxorubicin (DOX); however, it is unknown whether switching from a high-fat diet to a low-fat diet can attenuate the intensified DOX cardiotoxicity. The purpose of this study was to investigate the effects of a low-fat diet on DOX-induced cardiotoxicity in rats previously fed a high-fat diet.

Methods: Male rats were randomly assigned to consume a Western diet or a low-fat diet for 6 weeks. Western diet-fed rats were then further randomized to switch to the low-fat diet (WD-LF) or continue with the Western diet (WD). One week later, WD-LF and WD received 1 mg/kg DOX per day for 10 consecutive days and continued with their diets (WD-LF + DOX, WD + DOX). LF was further randomized to receive 1 mg/kg DOX per day for 10 consecutive days (LF + DOX) or saline injections as a control (LF + SAL). Four weeks following the first injection, cardiac function was analyzed, and left ventricles were analyzed for cardiotoxicity indices.

Results: When compared to LF + SAL and LF + DOX, WD + DOX exhibited an enhanced cardiotoxicity as evidenced by reduced septal wall thickness, fractional shortening, and sarco-endoplasmic reticulum Ca(2+) ATPase expression as well as increased left ventricular cavity dimensions, lipid peroxidation, and β-myosin heavy-chain expression. This exacerbated cardiotoxicity was not observed in WD-LF + DOX.

Conclusions: Switching to a low-fat diet 1 week prior to, during, and following DOX treatment attenuated the exacerbated cardiotoxicity observed in the previously Western diet-fed rats.
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http://dx.doi.org/10.1007/s00280-013-2154-5DOI Listing
June 2013

Rehabilitative exercise in a rat model of doxorubicin cardiotoxicity.

Exp Biol Med (Maywood) 2012 Dec;237(12):1483-92

School of Sport and Exercise Science, University of Northern Colorado, Greeley, CO 80639, USA.

The use of exercise to minimize doxorubicin (DOX)-induced cardiotoxicity is gaining attention. However, very few clinically relevant reports exist investigating the effects of exercise performed during and following DOX treatments. The purpose of this study, therefore, was to examine the effects of voluntary wheel running during and following DOX treatment using two models of late-onset DOX cardiotoxicity in the rat. Female Sprague-Dawley rats received either DOX or saline injections using one of two separate treatment regimens. These regimens involved either daily or weekly DOX injections with cumulative doses for both protocols totaling 15 mg/kg. Daily DOX injections were 1 mg/kg and lasted for 15 consecutive days while weekly DOX injections were 2.5 mg/kg and lasted for six consecutive weeks with control animals receiving matched saline injection regimens. Immediately following the initial DOX/saline injection, animals were randomly housed in cages with voluntary running wheels or standard rat cages throughout DOX/saline treatments and continued until reaching 10 weeks. Cardiac function was then assessed using echocardiography and an isolated working heart model, and myosin heavy chain (MHC) isoform distribution was assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. When compared wth controls, daily DOX treatment resulted in reduced running wheel distances at weeks 2-10 (P < 0.05), and weekly DOX treatment resulted in reduced running wheel distances at weeks 2, 6 and 10 (P < 0.05). Nonetheless, wheel running during and following daily and weekly DOX dosing protected against DOX-induced cardiotoxicity by preserving maximal mitral and aortic blood flow velocities, left ventricular developed pressure and MHC isoform expression. In conclusion, the overall reduced volume of activity during and following daily and weekly DOX treatments attenuated DOX-induced cardiac dysfunction suggesting that low-volume endurance training may be an effective rehabilitative approach in minimizing DOX cardiotoxicity in cancer patients.
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http://dx.doi.org/10.1258/ebm.2012.012137DOI Listing
December 2012

Voluntary wheel running in growing rats does not protect against doxorubicin-induced osteopenia.

J Pediatr Hematol Oncol 2013 May;35(4):e144-8

School of Sport and Exercise Science, University of Northern Colorado, Greeley, CO 80639, USA.

There is growing concern regarding the long-term negative side effects of chemotherapy in childhood cancer survivors. Doxorubicin (DOX) is commonly used in the treatment of childhood cancers and has been shown to be both cardiotoxic and osteotoxic. It is unclear whether exercise can attenuate the negative skeletal effects of this chemotherapy. Rat pups were treated with saline or DOX. Animals remained sedentary or voluntarily exercised. After 10 weeks, femoral bone mineral content and bone mineral density were measured using dual-energy x-ray absorptiometry. Cortical and cancellous bone architecture was then evaluated by microcomputed tomography. DOX had a profound negative effect on all measures of bone mass and cortical and cancellous bone architecture. Treatment with DOX resulted in shorter femora and lower femoral bone mineral content and bone mineral density, lower cross-sectional volume, cortical volume, marrow volume, cortical thickness, and principal (IMAX, IMIN) and polar (IPOLAR) moments of inertia in the femur diaphysis, and lower cancellous bone volume/tissue volume, trabecular number, and trabecular thickness in the distal femur metaphysis. Exercise failed to protect bones from the damaging effects of DOX. Other modalities may be necessary to mitigate the deleterious skeletal effects that occur in juveniles undergoing treatment with anthracyclines.
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http://dx.doi.org/10.1097/MPH.0b013e318279b1fbDOI Listing
May 2013

Tissue retention of doxorubicin and its effects on cardiac, smooth, and skeletal muscle function.

J Physiol Biochem 2013 Jun 14;69(2):177-87. Epub 2012 Aug 14.

School of Sport and Exercise Science, University of Northern Colorado, Greeley, CO 80639, USA.

Cancer-related fatigue is a pervasive syndrome experienced by a majority of cancer patients undergoing treatment, and muscular dysfunction may be a key component in the development and progression of this syndrome. Doxorubicin (DOX) is a commonly used antineoplastic agent used in the treatment of many cancers. The purpose of this study was to determine the effect of DOX exposure on the function of cardiac, skeletal, and smooth muscle tissues and examine the role accumulation of DOX may play in this process. In these studies, rats were treated with DOX and measurements of cardiac, skeletal, and smooth muscle function were assessed 1, 3, and 5 days after exposure. All muscular tissues showed significant and severe dysfunction, yet there was heterogeneity both in the time course of dysfunction and in the accumulation of DOX. Cardiac and skeletal muscle exhibited a time-dependent progressive decline in function during the 5 days following DOX treatment. In contrast, vascular function showed a decline in function that could be characterized as rapid onset and was sustained for the duration of the 5-day observation period. DOX accumulation was greatest in cardiac tissue, yet all muscular tissues showed a similar degree of dysfunction. Our data suggest that in muscular tissues both DOX-dependent and DOX-independent mechanisms may be involved with the muscular dysfunction observed following DOX treatment. Furthermore, this study highlights the fact that dysfunction of skeletal and smooth muscle may be an underappreciated aspect of DOX toxicity and may be a key component of cancer-related fatigue in these patients.
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http://dx.doi.org/10.1007/s13105-012-0200-0DOI Listing
June 2013

Exercise training mitigates anthracycline-induced chronic cardiotoxicity in a juvenile rat model.

Pediatr Blood Cancer 2012 Jul 2;59(1):149-54. Epub 2011 Nov 2.

School of Sport and Exercise Science and the Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, Colorado 80639, USA.

Background: Childhood cancer survivors are at greater risk of cardiovascular complications once they reach adulthood. Anthracyclines may be a major contributor to these delayed-onset complications, yet their use continues because of favorable clinical outcomes. Exercise has been shown to protect against anthracycline cardiotoxicity, yet it is unclear whether exercise can protect against delayed-onset cardiotoxicity when treatment is initiated in childhood. The aim of the present study was to determine if exercise training provides cardioprotection in a juvenile rat model of delayed-onset anthracycline cardiotoxicity.

Procedure: At 25 days of age, male Sprague-Dawley rat pups were subjected to a treatment regimen with the anthracycline doxorubicin (DOX). Pups received DOX at 2 mg/kg on 7 consecutive days (cumulative dose 14 mg/kg) or saline as a control. At the time DOX treatment began, pups remained sedentary or were allowed to voluntarily exercise. Ten weeks after the initiation of exercise, cardiac function was assessed both in vivo and ex vivo.

Results: DOX treatment stunted normal growth and significantly impaired cardiac function. While voluntary exercise did not offset changes in the growth curve, it did provide significant cardioprotection against DOX-induced cardiotoxicity.

Conclusions: Exercise training, initiated at the time treatment begins, can protect against delayed-onset anthracycline-induced cardiotoxicity in adult rats that were treated with anthracyclines as juveniles.
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http://dx.doi.org/10.1002/pbc.23392DOI Listing
July 2012
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