Recent Publications & Abstracts
- Schneider CM. Management of Cancer Rehabilitation Programs. ACSM Resource Manual for Cancer Rehabilitation Certification, Chapter 10, 2012.
- Hayward R, Lien C-Y, Jensen BT, Hydock DS, Schneider CM. Exercise Training Mitigates Anthracycline-Induced Chronic Cardiotoxicity in a Juvenile Rat Model. Pediatric Blood & Cancer 59: 149-154, 2012.
- Hayward R, Hydock DS, Gibson N, Greufe S, Bradel E, Parry TL. Tissue Retention of Doxorubicin and its Effects on Cardiac, Smooth, and Skeletal Muscle Function. Journal of Physiology and Biochemistry (in press).
- Hayward R, Iwaniec U, Turner RT, Lien C-Y, Jensen BT, Hydock DS, Schneider CM. Voluntary Wheel Running in Growing Rats Does Not Protect Against Doxorubicin-Induced Osteopenia. Journal of Pediatric Oncology & Hematology (in press).
- Hayward R, Lien C-Y. Echocardiographic Evaluation of Cardiac Structure and Function During Exercise Training in the Developing Sprague-Dawley Rat. Journal of the American Association for Laboratory Animal Science 50:454-461, 2011.
- Hydock DS, Parry T, Jensen B, Lien C-Y, Schneider CM, Hayward R. Effects of Endurance Training on Combined Goserelin Acetate and Doxorubicin Treatment-Induced Cardiac Dysfunction. Cancer Chemotherapy and Pharmacology 68: 685-692, 2011
- Hydock DS, Lien C-Y, Jensen BT, Schneider CM, Hayward R. Characterization of the Effect of In Vivo Doxorubicin Treatment on Skeletal Muscle Function in the Rat. Anticancer Research 31: 2023-2028, 2011.
- Hydock DS, Lien CY, Jensen BT, Schneider CM, Hayward R. Exercise Preconditioning Provides Long-Term Protection Against Early Chronic Doxorubicin Cardiotoxicity. Integrative Cancer Therapies 10:47-57, 2011.
- Schmitz, KH, Courneya, KS, Matthews, C, Demark-Wahnefried, W., Galvao, DA., Pinto, BM, Irwin, ML, Wolin, KY, Segal, RJ, Lucia, A, Schneider, CM, Von Gruenigen VE, Schwartz, AL. American College of Sports Medicine Roundtable on Exercise Guidelines for Cancer Survivors. Medicine & Science in Sports & Exercise 42(7):1409-1426, 2010.
- Sprod LK, Hsieh CC, Hayward R, Schneider CM. Three vs. Six Months of Exercise Training in Cancer Survivors. Breast Cancer Research and Treatment 121:412-419, 2010.
- Schneider CM, Hayward R. Cancer. In Exercise Physiology: From a Cellular to an Integrative Approach. Eds. Philippe Connes, Olivier Hue, Stéphane Perrey. IOC Press, 2010.
Physiological and Psychological Responses to a Longitudinal Rehabilitation Program
Jessica M. Brown1, Trent L. Lalonde1, Kurt Dallow 1,2 FACSM, Reid Hayward1, Carole M. Schneider1 FACSM. 1Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO. 2 North Colorado Family Medicine, Greeley, CO.
Physiological and psychological improvements have been well noted in cancer survivors after an exercise intervention. To date, little research has been done on the effects of a long-term exercise training program. PURPOSE: To assess the physiological and psychological responses to exercise training in cancer survivors over a 21 month exercise intervention. METHODS: Thirty-four cancer survivors, including 9 males and 24 females, participated in a cancer rehabilitation program consisting of 60 minute exercise training sessions, three days per week for 21 months. Each session included cardiovascular, muscular strength, muscular endurance, flexibility, and balance training. Physiological and psychological assessments which examined cardiorespiratory fitness, muscular endurance, depression, fatigue, and quality of life were conducted at the onset of the program (INTL), at three months (1ST), and every six months until four reassessments were completed (2ND, 3RD, and 4TH, respectively.) RESULTS: Significant improvements were observed in all measures (p<0.05), except muscular endurance. Cardiovascular endurance improved 12.1% (p=.002) at onset (INTL to 1ST) and although additional improvement occurred, it was not significant. Likewise, total fatigue decreased -33.9% (p<.0001) from INTL to 1ST while subsequent improvements were not significant. Depression was shown to decrease -17.9% (p=.043) and -17.6% (p=.025) from INTL to 1ST and 3RD to 4TH, respectively. Although the main effects for muscular endurance yielded no significance, pairwise comparisons revealed a 32.9% improvement from INT to 1ST (p=0.011). Total quality of life did not improve at onset, but a significant 10.1% increase (p=.006) occurred from 2ND to 3RD reassessments. CONCLUSION: A 21 month full-body exercise program has been shown to elicit improvements in physiological and psychological measures in cancer survivors. The greatest improvements occur during the first three months of training then plateau. This suggests that a 3-month exercise intervention is sufficient to return cancer survivors to normal functional capacity.
The Effect of Preconditioning on Initial Physiological and Psychological Assessments following Treatment
Brent M. Peterson1, Trent L. Lalonde1, Kurt Dallow1,2 FACSM, Reid Hayward1 and Carole M. Schneider1 FACSM. 1Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO. 2 North Colorado Family Medicine, Greeley, CO.
Exercise has been associated with the improvement of various physiological and psychological variables in cancer survivors post cancer treatment. However, little information exists on the role prior physical activity may have on functional capacity. PURPOSE: To assess the differences between prior physical activity and the initial physiological and psychological assessments in cancer survivors following treatment. METHODS: A total of 412 cancer survivors that had undergone radiation and/or chemotherapy were eligible for this study. Participants completed comprehensive physical assessments and Piper fatigue and Beck depression inventories. Functional capacity was determined during an initial assessment including VO2peak (multistage treadmill protocol). Prior physical activity (PA) was defined as being none (1), low (2), and moderate (3) based on frequency, intensity, and duration according to the ACSM guidelines. A multivariate analysis of variance (MANOVA) determined the group variance differences. RESULTS: There was a significant (p<.05) main effect for prior PA. Post hoc pairwise comparisons determined that there were significant (p<.05) differences between groups 1 and 3 for VO2peak (21.23 ± 6.70 vs. 23.46 ± 7.02 mL·kg·-1·min-1, respectively), groups 1 and 3, and groups 2 and 3 for fatigue (5.09 ± 2.23 vs. 4.28 ± 2.19 and 5.07 ± 2.03 vs. 4.28 ± 2.19, respectively) and groups 1 and 3 for depression (12.03 ± 7.74 vs. 9.90 ± 6.19, respectively). Moderately active individuals showed greater initial assessment values for functional capacity (VO2peak). Additionally, greater decreases were observed in fatigue and depression in the moderate activity group. CONCLUSION: Cancer treatment-related side-effects lengthen the recovery process post treatment for cancer survivors. The results of this study demonstrate the importance of moderate prior physical activity for the attenuation of treatment-related reductions in functional capacity, fatigue and depression.
Validation of the Rocky Mountain Cancer Rehabilitation Institute Multistage Treadmill Protocol for Cancer Survivors
Daniel Y.K. Shackelford1, Jessica M. Brown1, Trent Lalonde1, David S. Hydock1, Carole M. Schneider1 FACSM. 1Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO. 2North Colorado Family Medicine, Greeley, CO.
Currently there is not a multistage treadmill protocol for cancer survivors. Most protocols have stages that are either too high in intensity or too long in duration and are highly stressful for cancer survivors. The Rocky Mountain Cancer Rehabilitation Institute (RMCRI) developed a treadmill protocol designed specifically for cancer survivors to address this issue. PURPOSE: To validate the RMCRI multistage treadmill protocol for cancer survivors. METHODS: Fifteen cancer survivors completed a randomized double validation study to compare oxygen consumption (VO2peak) between two protocols. The RMCRI treadmill protocol, using gas analysis to determine VO2peak, was validated against the Bruce protocol. Participants completed the randomized trials one week apart in random order. The Bruce protocol VO2peak was then compared with the VO2peak recorded from the gas analysis for the RMCRI treadmill protocol. Additionally, ACSM’s predicted VO2peak equations were validated against the RMCRI protocol using gas analysis. RESULTS: No significant differences (p=.98) in VO2peak were found between the RMCRI protocol and the Bruce protocol and these values were significantly correlated with the RMCRI gas analysis test (R2=.712, p=.003). The VO2peak achieved using RMCRI gas analysis compared to ACSM’s predicted VO2peak equations showed no significant difference (p=.72). The VO2peak values obtained with ACSM’s predicted VO2peak equations were significantly correlated with the VO2peak values from the RMCRI protocol gas analysis (R2=.830, p<.001). This suggests ACSM’s predicted equations may be used in place of gas analysis for the RMCRI protocol. CONCLUSION: The RMCRI multistage treadmill protocol which has shorter stages and lower intensities was better tolerated and less stressful for cancer survivors. Given the validity and strong correlations to other treadmill protocols, the RMCRI cancer specific protocol should be the standard for the determination of functional capacity (VO2peak) in cancer survivors.
The Effect Prior Physical Activity has on Physiological and Psychological Outcomes in Cancer Survivors
Andrew R. Smith1, Trent L. Lalonde1, Brent M. Peterson1, Jessica M. Brown1, Reid Hayward1 FACSM, Kurt Dallow1,2 FACSM, Carole M. Schneider1 FACSM. 1Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO. 2North Colorado Family Medicine, Greeley, CO.
Cancer survivors are impacted by physical and emotional responses associated with diagnosis and treatment. Current research shows that exercise provides a positive effect in cancer survivors at various stages in their recovery. PURPOSE: To investigate the effect physical activity level prior to beginning a cancer rehabilitation program has on physiological and psychological outcomes in cancer survivors following a supervised 3-month exercise intervention. METHODS: Two hundred forty-seven cancer survivors participated in initial fitness assessments examining heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP), cardiorespiratory fitness (VO2peak), and abdominal strength (crunches). In addition, subjects completed inventories assessing fatigue and depression. Subjects were divided into three groups based on self-reported physical activity prior to the initial assessment; none (no prior physical activity), low (< 150 minutes of prior physical activity per week), and moderate (≥ 150 minutes of prior physical activity per week) according to ACSM guidelines. Subjects were given an individualized exercise prescription and participated in 3 months of supervised exercise. Subjects were reassessed following the 3-month intervention. RESULTS: No significant differences (p>.05) were found between prior physical activity and any of the physiological or psychological variables assessed following the 3-month intervention. However, significant improvements (p<.01) were found when comparing percent change pre to post 3-month exercise in all physiological and psychological variables [HR (-2.56%), SBP (-1.45%), DBP (-1.20%), VO2peak (+17.51%), crunches (+60.53%), fatigue (-2.13%), and depression (-2.24%)]. CONCLUSION: The results of this study suggest that cancer survivors demonstrate improved physiological and psychological outcomes following a supervised three-month exercise intervention regardless of their physical activity level prior to entering a cancer rehabilitation program.
Initial Physiological and Psychological Measures in Cancer Survivors During Treatment Versus Following Treatment
Colin J. Quinn1, Jessica M. Brown1, Trent L. Lalonde1, Kurt Dallow1,2, FACSM, Reid Hayward1, Carole M. Schneider1, FACSM. 1Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO. 2North Colorado Family Medicine, Greeley, CO.
There have been suggestions that once cancer survivors complete treatment that exercise interventions can be similar to the apparently healthy population. This implies that the negative effects of cancer treatments occur during treatment with no lingering side-effects once treatment is completed. PURPOSE: To compare cancer survivors’ initial physiological and psychological assessment values during treatment to the initial values of cancer survivors’ following treatment. METHODS: Five hundred eighty-one cancer survivors participated in initial fitness assessments examining pulmonary function, cardiorespiratory fitness (VO2peak), muscular strength, resting heart rate and blood pressure. Additionally, participants completed inventories of depression, fatigue, and quality of life. Participants were separated into two groups, those who were in treatment (n=99) and those who had completed treatment (n=482). RESULTS: Significant differences were found on the initial assessment values between groups for VO2peak (p<.05). Cancer survivors in treatment exhibited higher VO2peak scores (24.06±.76 ml/kg/min) on the initial assessment compared to cancer survivors who had completed treatment (21.97±.33 ml/kg/min). No significant differences were found in measures of pulmonary function, muscular strength, resting heart rate and blood pressure. Initial psychological parameters (depression, fatigue, quality of life) were not significantly different between groups. CONCLUSION: The higher initial VO2peak values for cancer survivors during treatment suggest that the cumulative negative effects of cancer treatments occur throughout the treatment regimen. Cancer survivors following treatment have cumulative negative side-effects and therefore need to participate in an exercise intervention designed specifically for cancer survivors.
Effects of Reduced Dietary Fat Intake on Doxorubicin Cardiotoxicity in Previously High Fat Fed Rats
David S. Hydock1, Chia-Ying Lien2, Brock T. Jensen3, Carole M. Schneider1, FACSM, Reid Hayward1. 1University of Northern Colorado, Greeley, CO; 2National University of Taiwan, Taipei, Taiwan, 3Slippery Rock University, Slippery Rock, PA.
It has been reported that the cardiotoxicity associated with the anti-cancer drug doxorubicin (DOX) is exacerbated with high dietary fat intake. Very little work has been done examining protective approaches against DOX cardiotoxicity with high-fat feeding, but it was hypothesized that reducing dietary fat intake in previously high-fat fed rats would minimize this exacerbated DOX cardiotoxicity. PURPOSE: To examine the effects of a low-fat diet on DOX-induced cardiotoxicity in previously high-fat fed rats. METHODS: Male Sprague-Dawley rats were randomly assigned to consume a high-fat diet (HF, 42% kcal from fat, n=23) or a low-fat diet (LF, 11% kcal from fat, n=20) ad libitum for 6 weeks. HF animals were then further randomized to switch to the low-fat diet (HF-LF, n=11) or continue with high-fat feeding (HF-HF, n=12). One week later, HF-HF and HF-LF received 1 mg/kg DOX (i.p.) per day for 10 consecutive days and were allowed to continue with either high-fat (HF-HF+DOX) or low fat (HF-LF+DOX) feeding, respectively. LF was further randomized to receive 1 mg/kg DOX (i.p.) per day for 10 consecutive days (LF+DOX, n=10) or saline injections as a control (LF+SAL, n=10). Four weeks following the first injection, cardiac function was analyzed in vivo using echocardiography or ex vivo using an isolated working heart model. RESULTS: When compared to LF+SAL, there was a significant decrease in fractional shortening (-18%, p<0.05), relative wall thickness (-35%, p<0.01), and mean aortic blood flow velocity (-16%, p<0.05) in HF-HF+DOX. When compared to LF+SAL, these significant reductions in fractional shortening, relative wall thickness, and mean aortic blood flow velocity were not observed in HF-LF+DOX (-7%, -18%, and -8%, respectively, p>0.05). Left ventricular developed pressure (LVDP) and +dPdt in LF+SAL were 104±3 mmHg and 3510±161 mmHg/s, respectively, and significantly lower LVDP and +dPdt were observed in HF+DOX (70±5 mmHg and 2601±142 mmHg/s, respectively, p<0.001). These reductions were attenuated in HF-LF+DOX (81±3 mmHg and 2793±95 mmHg, respectively) when compared to LF+SAL (p<0.01). CONCLUSION: Switching to a low-fat diet one week prior to, during, and following DOX treatment attenuated the cardiotoxicity observed in previously high-fat fed rats.
Time Course of Doxorubicin Accumulation and Dysfunction in Left Ventricular Tissue
Noah M. Gibson, David S. Hydock, Stephanie E. Greufe, Carole M. Schneider, FACSM, Reid Hayward: Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO.
PURPOSE: The purpose of this study was to determine if the degree of initial DOX accumulation and subsequent rate of clearance in the left ventricle (LV) contribute to cardiac dysfunction and its progression. METHODS: Male Sprague-Dawley rats were randomly assigned to receive 15mg DOX/kg body weight or saline (SAL); DOX rats were further randomized to be sacrificed 1, 3 or 5 days post treatment. Isolated working heart experiments were performed to determine cardiac function. LV DOX accumulation was quantified using reversed phase high performance liquid chromatography (HPLC). HPLC was performed within 24 hours of sacrifice. A multiple linear regression model was fit to the data to determine if accumulation and days post treatment significantly contributed to the degree of dysfunction. RESULTS: Significant differences were observed in left ventricular developed pressure (LVDP) between SAL (100±16 mmHg), and DOX groups (p<0.05), with no LVDP differences between 1-day (78±19 mmHg), 3-days (77±20 mmHg) and 5-days (85±14 mmHg) post DOX treatment. LV DOX accumulation was greatest 1-day post DOX treatment (875±303 ng DOX/g LV tissue) and was significantly reduced at 3-days (610±210 ng DOX/g LV tissue) and 5-days (342±126 ng DOX/g LV tissue) post treatment (p<0.05). CONCLUSIONS: These results suggest that while the accumulation of DOX in the first 24 hours following exposure induces cardiac dysfunction, the degree of dysfunction is not related to the quantity of DOX accumulation during the first 5 days after treatment.
Voluntary Wheel Running Does Not Protect Against Doxorubicin-Induced Osteopenia in the Growing Rat
Traci L. Parry,1 Urszula T. Iwaniec,2 Russell T. Turner, 2 Chia-Ying Lien,3 Brock T. Jensen,4 David S. Hydock,1 Carole M. Schneider FACSM,1 Reid Hayward1: 1University of Northern Colorado, School of Sport and Exercise Science and the Rocky Mountain Cancer Rehabilitation Institute, Greeley, Colorado; 2Skeletal Biology Laboratory, Oregon State University, Corvallis, Oregon; 3National Taiwan University, Athletic Department, Taipei, Taiwan; 4Slippery Rock University, Slippery Rock, Pennsylvania
Despite numerous negative side effects, including osteopenia, doxorubicin (DOX) continues to be used clinically because of its high success rate in the treatment of an array of cancers. At this time it is unclear whether exercise can attenuate the deleterious effects of DOX on bone architecture. PURPOSE: To determine whether voluntary wheel running attenuates the negative effects of DOX on bone in growing male rats. METHODS: Male Sprague-Dawley rat pups (25 days old) were randomly assigned to one of four groups: sedentary control, SED+C; sedentary DOX, SED+DOX; voluntary wheel run control, WR+C; and voluntary wheel run DOX, WR+DOX. Animals received 2 mg/kg DOX i.p. or an equivalent volume of saline (1 mL) over 7 successive days. Beginning with the first day of injections, SED animals did not exercise while animals in WR groups were allowed free access to cage-mounted running wheels for a total of 10 weeks. Upon completion of the protocol, animals were sacrificed and tibia and femur excised for assessment of bone mineral content and density (tibia) via dual energy x-ray absorptiometry and cancellous and cortical bone architecture (femur) via micro computed tomography. RESULTS: WR+C animals ran an average of 23 ± 3 km/wk while WR+DOX animals ran an average of 12 ± 3 km/wk. Treatment with DOX resulted in significantly lower tibial length and tibial bone mineral content and density (p < 0.05) compared to SED+C. The negative effects of DOX were observed in both the cortical and cancellous envelopes. Midhshaft femur cortical cross-sectional area, cortical volume, and polar moment of inertia were significantly lower in DOX-treated rats compared to SED+C. Distal femur metaphysis cancellous bone volume/tissue volume was also lower in DOX-treated compared to SED+C rats. Voluntary wheel running did not protect against the detrimental effects of DOX treatment on the skeleton in developing rats. CONCLUSIONS: DOX treatment in male rat pups suppressed bone growth and resulted in cancellous and cortical osteopenia. Voluntary wheel running during this time did not protect the growing skeleton against the negative effects of DOX treatment.
Effects of Calorie Restriction and Voluntary Exercise on Doxorubicin-Induced Cardiac Dysfunction
Stephanie E. Greufe, Noah Gibson, Traci Parry, David S. Hydock, Carole M. Schneider, and Reid Hayward. School of Sport and Exercise Science and the Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley, CO, 80639.
Calorie restriction is the only proven non-genetic means to life extension. One of the most widely accepted theories explaining this extension is a decrease in tissue damage caused by oxidative stress. Oxidative stress has been shown to contribute to cardiac dysfunction in those treated with doxorubicin and this dysfunction can be attenuated with exercise training. PURPOSE: The purpose of this study was to determine the effect of calorie restriction on doxorubicin-induced cardiac dysfunction and the combined effects of calorie restriction and voluntary exercise on doxorubicin-induced cardiac dysfunction. METHODS: Female rats were given 24 hour access to a running wheel (WR) or remained sedentary (SED) for 4 months. During those 4 months animals were divided into 2 groups, those fed ad libitum (AL) and those restricted to 60% of the intake of the ad libitum animals (CR). At the completion of the 4 month treatment animals were injected with either doxorubicin (15 mg/kg; DOX) or saline (0.9% NaCl; SAL). Five days following the injection animals were sacrificed. Cardiac function was measured with the working heart model and HPLC was used to quantify the accumulation of DOX in left ventricular tissue. RESULTS: Body mass was significantly lower in the CR groups. Animals in the calorie restricted group ran significantly more than those in the AL group. Left ventricular developed pressure (LVDP) (53.6%, p< .05), end systolic pressure (ESP) (53.7%, p< .05) and LV maximal rate of pressure development (dP/dt max) (57.3%, p< .05) were significantly increased in the CR.SED.DOX group when compared to AL.SED.DOX. LVDP (79.3%, p< .001), ESP (82.4%, p< .001), dP/dt max (65.1%, p< .01) and dP/dt min (76.9%, p< .01) were significantly higher in the CR.WR.DOX group compared to the AL.SED.DOX group. In addition, the CR.WR.DOX group showed significantly higher LVDP (41.2%, p< .01), ESP (38.7%, p< .01) and dP/dt min (73.7%, p< .05) compared to the AL.WR.DOX group. DOX accumulation in the heart was significant 5-fold decrease (p< .05) in the CR.WR.DOX group compared to the AL.SED.DOX group. CONCLUSION: Separately, both calorie restriction and voluntary exercise protected against DOX-induced cardiac dysfunction, and the combination of calorie restriction and voluntary exercise provides further protection beyond that of either one alone.
Time Course of Doxorubicin Accumulation and Dysfunction in the Rat Aorta
Noah M. Gibson, David S. Hydock, Reid Hayward: 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 due to dose-dependent acute and chronic cardiovascular toxicity. However, little is known about the mechanisms of DOX induced vascular dysfunction. The purpose of this study was to determine if DOX accumulates in vascular tissue and contributes to the onset and progression of vascular dysfunction over time. Male Sprague-Dawley rats were randomly assigned to receive 15 mg DOX/kg of body mass or saline (SAL); DOX rats were further randomized to be sacrificed 1, 3 or 5 days post treatment. Isolated aortic rings were used to examine vascular function, and aortic DOX accumulation was quantified using high performance liquid chromatography. While DOX did in fact accumulate in vascular tissue (204±89 ng DOX/g LV) within 24 hours, there was no significant difference in accumulation over time (183±107 ng DOX/g LV at 3 days; 156±60 ng DOX/g LV at 5 days). There were significant differences between SAL and DOX groups (p<0.05) in vasoconstriction, endothelium-dependent and -independent vasodilation, however there were no functional differences over time with DOX treatment. Our results show that there is early-onset, sustained vascular dysfunction during the 5 days following DOX treatment, which is accompanied by a sustained accumulation of DOX in vascular tissue.
Intramuscular Doxorubicin Accumulation and Skeletal Muscle Function
Eric Bredahl, Noah Gibson, Stephanie Greufe, Keith Pfannenstiel, Traci Parry, Carole Schneider, Reid Hayward, and David Hydock. University of Northern Colorado. School of Sport and Exercise Science and the Rocky Mountain Cancer Rehabilitation Institute, Greeley CO, USA.
Doxorubicin (DOX) is powerful anthracycline antibiotic used to treat a wide variety of cancers. DOX has been linked to debilitating side effects, and recent studies have reported a DOX-induced decline in skeletal muscle function. However, the connection between intramuscular DOX accumulation and muscle dysfunction has yet to be determined. PURPOSE: To evaluate the effects of DOX on type I and type II muscle function and DOX accumulation. METHODS: Male Sprague-Dawley rats received 15 g/kg DOX i.p. (n=27) or an equivalent volume of saline i.p. as a control (CON, n=11). Soleus (SOL) and extensor digitorum longus (EDL) function was assessed ex vivo 1 day (n=9), 3 days (n=10), or 5 days (n=8) post DOX injections. DOX accumulation in skeletal muscle was then assessed using high performance liquid chromatography. RESULTS: No significant SOL or EDL maximal twitch force differences were observed 1 day or 3 days post DOX when compared to CON (p>0.05). However, SOL maximal twitch force 5 days post DOX was significantly lower than CON (19±5 mN vs. 39±3 mN, respectively, p<0.01), and EDL maximal twitch force 5 days post DOX was significantly lower than CON (34±4 mN vs. 76±8 mN, respectively, p<0.01). SOL DOX accumulation at 1, 3, and 5 days post injection was (in ng DOX/g of tissue) 425±32, 299±67, and 117±24, respectively whereas EDL DOX accumulation at 1, 3, and 5 days post injection was (in ng DOX/g of tissue) 269±35, 147±29, and 166±45, respectively. The only significant DOX accumulation difference observed between SOL and EDL was at day 1 (p<0.01). Significant reductions in intramuscular DOX levels were observed in SOL between days 1 and 5 (p<0.01) and days 3 and 5 (p<0.05), but significant reductions in intramuscular DOX levels were not observed between days 1, 3, or 5 in the EDL (p>0.05). CONCLUSION: Although DOX treatment resulted in depressed skeletal muscle function in both the SOL and EDL, differences in intramuscular DOX accumulation and clearance were observed between the SOL and EDL. DOX levels were higher in the SOL when compared to EDL, but this elevated level also declined significantly over time in the SOL suggesting differential accumulation and clearance of DOX in type I and type II muscle.
Effects of Voluntary Wheel Running on Aortic Doxorubicin Accumulation and Dysfunction
Noah M. Gibson, Stephanie E. Greufe, David S. Hydock, Carole M. Schneider, FACSM, Reid Hayward: 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. However, its use is limited due to dose-dependent cardiovascular toxicity. While it is known that exercise preconditioning reduces the severity of DOX-induced cardiotoxicity, it is unknown as to whether it can help mitigate DOX-induced vasculotoxicity. The purpose of this study was to determine if exercise reduces the degree of DOX-induced dysfunction and its accumulation within vascular tissue. Ten week old male Sprague-Dawley rats were randomly assigned to undergo 14-weeks of voluntary wheel running (WR) or remain sedentary (SED) and further randomized to receive 15 mg DOX/kg of body mass or equivalent saline (SAL) i.p. injection. Animals were sacrificed 24 hours post injection and isolated aortic rings were used to examine vascular function. Aortic DOX accumulation was quantified using high performance liquid chromatography (HPLC). Significant differences were found between WR-DOX and SED-DOX groups (p<0.05) with vasoconstriction and endothelium-independent vasodilation, however no differences (p>0.05) were found with endothelium-dependent vasodilation. There were also no differences in accumulation (WR-DOX 189±31 ng DOX/g aorta; SED-DOX 216±46 ng DOX/g aorta). These data suggest that exercise can help reduce the severity of vascular smooth muscle dysfunction but not endothelial dysfunction associated with DOX treatment and is independent of its accumulation.