Conference Paper

Effect of Exercise on T Cells in Cancer Survivors

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Abstract

PURPOSE: Cancer therapies increase the relative proportion of terminally differentiated senescent T cells relative to naive T cells. Our objective was to evaluate the effect of exer- cise on percentages of various T cell subsets in cancer survivors pre and post an exercise intervention. METHODS: Sixteen cancer survivors were recruited from the Rocky Mountain Cancer Rehabilitation Institute and completed a 12 week whole-body exercise training program. Prior to and upon completion blood was drawn and T cell phenotypes were analyzed by six color flow cytometry. RESULTS: All but one of the patients had completed treatment at the time of enrollment. Preliminary analysis shows a mean de- crease in the CD4:CD8 T cell ratio from 2.1 to 1.8 during the exercise intervention. CD8 senescent T cells decreased in 10 subjects while 6 had an increase. Unactivated, naïve CD8 T cells declined in 9 subjects and 7 subjects had an increase. This trend differs from CD4 naïve T cells, with 10 subjects having an increase in this cell subtype and 6 a de- crease. CONCLUSION: We are one of the first to evaluate chronic changes in the T cell compartment of cancer survivors who participate in ongoing exercise training. These very preliminary results suggest exercise may enhance immune function in cancer survivors by altering T cell proportions which are disrupted by adjuvant cancer therapies. Funded by a UNMC SAHP Pilot Research Grant.

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When compared with rested animals on days 3 and 6 (experiment 1) and days 6 and 9 (experiment 2) during forced swimming, significant decreases in mean thymic index in the exercised mice were evident. Thymuses from exercised animals were small and their cortex was thinned, but the density and appearance of the retained thymocytes appeared normal. There was no obvious necrosis of thymocytes. At 96 hr after cessation of forced swimming, thymic indices were similar, and normal thymic configuration returned. No discernible changes occurred in gross or histologic appearance of the spleen or in splenic indices. In 1956 Selye reported that rats forced to exercise severely on a treadmill developed atrophic thymuses, lymph nodes, and spleens. The data given in the present study do not define the mechanism for change in the size of the thymus and lack of change in the spleen during forced swimming. The change could be from stress-induced release of corticosteroids causing thymocyte lysis. Other mechanisms, such as altered T-cell circulation induced by exercise, are possible.
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Adriamycin produces clinically useful responses in a variety of human cancers including lymphomas, leukemias, and solid tumors. However, the toxicity of adriamycin has limited its usefulness. Iron-catalyzed free radical reactions as the peroxidation of membrane lipids, inactivation of critical enzymes, and the inhibition of DNA, RNA and protein synthesis in heart, liver and kidney have been implicated in the toxicity of adriamycin. In order to further assess the role of oxidative stress in the toxicity of adriamycin, the effects of adriamycin were examined on the urinary excretion of lipid metabolites at 0, 6, 12, 24, 48 and 72 h post-treatment, and on myocardial and hepatic lipid peroxidation and nuclear DNA single strand breaks at 24 h post-treatment following single oral and intravenous (i.v.) doses of 10 mg/kg adriamycin. Urinary malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT) and acetone (ACON) excretion was significantly increased at all time points examined. Following the oral administration of adriamycin, maximum excretion of MDA, FA, ACT and ACON of 6.2-, 2.7-, 3.7- and 2.2-fold relative to control values, respectively, occurred 24 h after treatment. However, following the i.v. administration of adriamycin, greatest increases in excretion of MDA, FA and ACT reaching 6.9-, 3.3- and 6.3-fold relative to control values, respectively, were observed 6 h after treatment, while the greatest increase in ACON excretion of 4.2-fold relative to control values occurred 12 h post-treatment. Following oral and i.v. administration of adriamycin, significant increases were observed in myocardial and hepatic lipid peroxidation in mitochondrial and microsomal membranes, and myocardial and hepatic nuclei DNA single strand breaks 24 h after treatment. The results indicate that adriamycin administration induces myocardial and hepatic lipid peroxidation which may be responsible for enhanced excretion of urinary lipid metabolites as a result of membrane damage, and also induces enhanced DNA damage. These effects may be due to adriamycin-induced production of reactive oxygen species.
Article
The effect of swimming-training upon the activities of the enzymes involved in the generation of reducing-equivalents (citrate synthase-mitochondria and glucose-6-phosphate dehydrogenase-cytosol) and of antioxidant enzymes (CuZn- and Mn-SOD, catalase and glutathione peroxidase) in the lymphoid organs (thymus, mesenteric lymph nodes and spleen) was examined. The skeletal muscles (soleus-red and gastrocnemius-white) were also studied. Although our data suggest an apparently random, organ-specific change in enzymatic activity, some interesting trends can be observed. Firstly, the increased citrate synthase and Mn-SOD activities observed in red, but not in white muscle, corroborate the well-known effect of endurance exercise-training on mitochondrial oxidative metabolism. Secondly, there was an inverse relationship between TBARs-monitored lipoperoxidation and glutathione peroxidase activity in all tissues studied, what is in accordance with the previous findings showing that such enzyme exerts the fine control of intracellular lipoperoxide concentration. Except in the case of the spleen, there was a trend for elevated glucose-6-phosphate dehydrogenase activity, coadjuvant of glutathione peroxidase in the antioxidant response to physical exercise in all tissues. Thirdly, Mn-SOD and catalase were conspicuously associated to oxidative stress in the thymus, while glutathione and catalase could be linked to this parameter in the spleen. Fourthly, the lymph nodes seem to be more dependent on the glucose-6-phosphate dehydrogenase/glutathione peroxidase pair for protection against damage promoted by physical exercise. Mn-SOD and catalase activities were lower in the lymph nodes after swimming training.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Exposure of murine thymocytes to doxorubicin (Dox) (0.5-1.0 microM, 24 hr) triggered rapid DNA degradation, as indicated by the appearance of a major subdiploid population demonstrated by DNA flow cytometry. Electron microscopic comparison of samples with large subdiploid populations versus those with little or no such subset revealed significantly more cells with the characteristic features of apoptosis, the morphologically definable stage of programmed cell death. These features include unipolar condensed chromatin, zeiosis, and electron-dense cytoplasm. Dox-induced apoptosis occurred without prior S or G2/M phase arrest or cell size increase. The subset most susceptible to Dox-induced apoptosis in vitro and in vivo was CD3-CD4+CD8+. The same subset is affected by dexamethasone (Dex); as reported for Dex-induced apoptosis, actinomycin D and cycloheximide also blocked Dox-induced apoptosis. Thymocytes exposed to higher Dox concentrations (2-10 microM) did not have a subdiploid population. Although at 2-10 microM Dox significantly reduced cell numbers (probably as a result of necrosis), at least 5-10% of the population was viable at 24 hr. Thymocytes exposed to low concentrations of Dox (0.001-1.0 microM) plus Dex (0.1 microM) exhibited additive induction of apoptosis, whereas those exposed to high concentrations of Dox (2-10 microM) plus Dex were completely devoid of any evidence of apoptosis. These results indicate that the Dox-induced killing in thymocytes (mostly noncycling cells) occurs via different mechanisms depending upon the Dox concentration.
Article
Thymic involution occurs in young adult male Wistar rats that have performed two runs to exhaustion (RTE) on a treadmill, separated by a 24-h rest period, but not after a single RTE. We were interested in determining whether programmed cell death (or apoptosis) is responsible for the corresponding decrease in T-cell numbers in the thymus. DNA fragmentation, which is an early feature of apoptosis and easily detected by agarose gel electrophoresis, was found in rat thymocytes after the second RTE (the duration of 1 RTE was approximately 5 h). It was also detected after a single RTE or after 2.5 h of running only, and the levels of DNA fragmentation were always roughly similar. In addition, DNA fragmentation was decreased in RU-486 vs. vehicle-treated rats that had run for 2.5 h. These results indicate that physical stress induces glucocorticoid receptor-mediated apoptosis of rat thymocytes. Because apoptosis is induced to similar levels during mild and severe physical stresses, some additional events must be associated to provoke thymic involution.
Article
This study was carried out to examine the effects of forced running exercise on the immune functions of male ICR mice. Mice aged 4 weeks were divided into two groups: a non-exercise group (control) and a group given forced running exercise (exercise group). The exercise applied was forced running at 15m/min on a flat floor without any slope for 60 min a day. The duration of exercise was 5 days per week for 12 weeks. The results obtained were as follows: 1) After 12 weeks of forced running exercise, the weight of the anterior tibialis muscle and succinate dehydrogenase activity in the anterior tibialis muscle increased significantly (p < 0.01) in the exercise group compared with the control group. A tendency for thymus weight to increase was shown in the exercise group, and liver and spleen weights were significantly (p < 0.01) greater than in the control group. 2) The potentiation of phagocytic function of the reticulo-endothelial system, examined by the carbon clearance method, was seen in the exercise group. 3) The ability of peritoneal macrophages (M phi) to phagocytose latex beads significantly increased (p < 0.01) in the exercise group. The acid phosphatase activity of peritoneal M phi remained in both groups. However, lactate dehydrogenase activity of peritoneal M phi significantly increased (p < 0.01) in the exercise group compared with the control group. 4) The proliferation of splenocytes induced by Con A in the exercise group significantly increased (p < 0.01) compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Apoptosis is a controlled form of cell death accompanied by distinct morphological and biochemical changes. In this study the nature of cytotoxicity induced by adriamycin (ADM) in rat thymocytes was evaluated. Morphological and biochemical changes characteristic of apoptosis were found to precede adriamycin-induced cell death. Our findings demonstrate the involvement of c-Myc, c-Jun, antioxidant enzymes CuZn superoxide dismutase and catalase, and perhaps poly ADP ribosylation in ADM-induced cell death.
Article
Post exercise lymphocytopenia is well documented and attributed to egress of lymphocytes from the vascular compartment. Recent studies have reported exercise induced DNA damage in leukocytes and have questioned a possible link to apoptosis. Eleven subjects underwent a ramped treadmill test to exhaustion. Venous blood samples were taken before, immediately post exercise, and 24 and 48 hours after exercise. Single cell gel electrophoresis revealed evidence of single strand DNA damage in 10% of lymphocytes immediately after exercise, but not at other times. Fluorescent microscopy showed three patterns of DNA distribution, similar to those seen in apoptosis, at all times after exercise. Three subjects underwent the same exercise protocol, and lymphocytes were prepared for flow cytometry to determine apoptosis using the TUNEL method. Flow cytometry revealed lymphocyte apoptosis in 63% of lymphocytes immediately after exercise and 86.2%, 24 hours after exercise. Lymphocyte apoptosis is documented for the first time after exercise and may in part account for exercise induced lymphocytopenia and reduced immunity.
Article
Lymphocyte apoptosis occurs in response to stressors such as thermal injury, trauma, sepsis, and surgery. This study evaluated the effect of a single bout of physical exercise stress on the induction of apoptosis in murine thymocytes and splenic lymphocytes. Female C57BL/6 mice, treadmill exercised at a submaximal intensity (35 m/min, 6% grade) for 90 min or serving as controls (walking on treadmill at 12 m/min, 6% grade, 5 min), were sacrificed 5 min or 120 min after completion of exercise. The percent of apoptotic, necrotic, and viable thymocytes and splenocytes were determined by flow cytometry using annexin V FITC and propidium iodide. There was a significantly higher percent of viable splenocytes in the mice sampled 120 min after cessation of exercise than treadmill control animals (p<0.05). In the thymus, there was a significantly lower percent of apoptotic (p<0.5) and a significantly higher percent of viable (p<0.05) cells in exercised mice sampled at 120 min after exercise relative to controls. Absolute numbers of thymocytes and splenocytes did not differ by exercise treatment condition. Plasma corticosterone levels were elevated immediately after exercise and were negatively correlated with the percent of viable lymphocytes in the spleen. During the time frame sampled, submaximal exercise is associated with a lower % of thymocytes expressing early markers of apoptosis, despite elevated plasma corticosterone levels. Retention of self-reactive, viable thymocytes which would normally be deleted or selective trafficking of apoptotic thymocytes out of the thymus may be involved in the exercise effect. Additional studies are necessary to identify the mechanisms for this shift in proportions of apoptotic and viable cells in lymphoid compartments with exercise.
Article
Reactive oxygen species may contribute to apoptosis in lymphoid tissues observed after exercise. Thymic and splenic tissues excised from control mice (C) or mice immediately after (t0) or 24 h after (t24) a run to exhaustion (RTE) were assayed for biochemical indexes of oxidative stress [thymic and splenic membrane lipid peroxides, superoxide dismutase, catalase, plasma uric acid (UA), and ascorbic acid (AA)]. There were significant increases in membrane lipid peroxides in thymus (P < 0.001) and spleen (P < 0.001) in acutely exercised mice relative to controls (thymus: C = 2.74 +/- 0.80 microM; t0 = 7.45 +/- 0.48 microM; t24 = 9.44 +/-1.41 microM; spleen: C = 0.48 +/- 0.22 microM; t0 = 1.78 +/- 0.28 microM; t24 = 2. 81 +/- 0.34 microM). The thymic and splenic tissue antioxidant enzymes concentrations of superoxide dismutase and catalase were significantly lower in samples collected at t0 relative to C and t24 mice (P < 0.001). Plasma UA and AA levels were used to assess the impact of the RTE on the peripheral antioxidant pool. There was no significant change in UA levels and a significant reduction in plasma AA concentrations (P < 0.001); the reduction in plasma AA occurred at t24 (6.53 +/- 1.64 microM) relative to t0 (13.11 +/- 0. 71 microM) and C (13.26 +/- 1.2 microM). These results suggest that oxidative damage occurs in lymphoid tissues after RTE exercise and that such damage may contribute to lymphocyte damage observed after acute exercise.
Article
Early Ca2+ signaling events in cells of the immune system after exhaustive exercise challenge (8% slope, 32 m/min(-1) speed) of female C57BL/6 mice, and their effects on oxidative reactions in thymus were studied. Intracellular Ca2+ and the oscillation of free extracellular Ca2+ were imaged with cell permeant cell and cell impermeant Fluo 3 calcium indicator in thymocytes. The role of estradiol was assessed by RIA for levels of membrane bound estradiol. Oxidative product release and membrane lipid peroxide were also evaluated. Intracellular Ca2+ levels were significantly higher in thymocytes of exercised compared with control mice (p < .001). There was a continuous flux of Ca2+ after exercise when cells were monitored in Ca2+ rich medium, with a significant influx between 160 and 200 sec (p < .001). Membrane bound estradiol was elevated in thymocytes of exercised compared to control mice (p < .05). Immediately after exercise there was a greater release of oxidative products by thymocytes in exhaustively exercised compared with control animals. There was also significant generation of lipid peroxide in thymus of exercised mice (p < .001). The findings suggest that exhaustive exercise may stimulate estradiol uptake by receptors on thymocytes, with a possible opening up of estradiol-receptor operated channels for Ca2+ entry into cells. This may have damaging effects on thymic lymphocytes by the triggering of oxidative reactions as determined by higher oxidative product release and greater generation of lipid peroxide.
Article
Two-month-old mice were placed in cages with (Ex) or without exercise running wheels with free access to the wheel 24 h/day for 10 mo. An equal amount of food for both groups was provided daily. Ex mice ran an average of 33.67 km/wk initially, and exercise decreased gradually with age. Ex mice had gained an average of 43.5% less body weight at the end of the experiment. Although serum lipid peroxides were not altered by exercise, superoxide dismutase and glutathione peroxidase activities in serum were significantly increased. Flow cytometric analysis of spleen cells revealed an increased percentage of CD8+ T cells and a decreased percentage of CD19+ B cells in Ex mice (P < 0.05). Exercise decreased apoptosis in total splenocytes and CD4+ cells incubated with medium alone or with H(2)O(2), dexamethasone, tumor necrosis factor-alpha (TNF-alpha), or anti-CD3 monoclonal antibody (P < 0.05) and CD8+ cells with medium alone or with TNF-alpha (P < 0.05). Even though exercise did not alter the intracellular cytokines (TNF-alpha and interleukin-2) or Fas ligand, it did significantly lower interferon-gamma in CD4+ and CD8+ cells (P < 0.05). In summary, voluntary wheel exercise appears to decrease H(2)O(2)-induced apoptosis in immune cells as well as decrease interferon-gamma production.
Article
The purpose of this study was to examine the relationship between active compared to inactive lifestyles and immunocompetence in men. Subjects, all male volunteers, regularly exercising moderately were separated into three age groups: young (20-39 years), middle-aged (40-59 years) and elderly (more than 60 years). Age-matched sedentary male subjects served as controls in each group. Immunological assessments were, total leucocyte count, lymphocyte subpopulation counts, natural killer cell activity and neutrophilic phagocytosis. Total leucocyte and T-cell (CD3+) counts were not significantly different among the groups. Among T-cell subsets, there was a slight increase in helper T-cell (CD3+CD4+) and a decrease in cytotoxic/suppressor T-cell (CD3+CD8+) concentrations in the older sedentary subjects, resulting in an age-associated significant increase in the CD4:CD8 ratio among those control groups. However, among the exerciser groups, no such increase and decrease in the T-cell subpopulations or an age-related increase of the CD4:CD8 ratio were observed. Considering the components of innate immunity, the concentration of NK-cells (CD16+CD56+) significantly increased in the elderly exercisers, compared to that of the age-matched control subjects, or of the young group. The phagocytotic activity of neutrophils showed an age-associated decline, but of lesser degree in the elderly exercisers than in the elderly controls. Taken together, these results suggest that habitual and moderate training in later life is associated with a lesser age-related decline in certain aspects of circulating T-cell function and innate immunity.
Article
To investigate the effect of training status on lymphocyte apoptosis as well as the expression of cell death receptors and ligands after a marathon run, and to compare these data with the alterations after treadmill exercise tests. Sixteen volunteers successfully finished the 2002 Münster marathon. Venous blood samples were drawn before and 0, 3, and 24 h after the race. After cell isolation, cell-based apoptosis markers annexin V, Fas receptor, and Fas ligand were measured by flow cytometry. The same parameters were investigated in a group of 10 subjects before, and 0 and 1 h after both an exhaustive (ExT) and a low-intensity (LoT) treadmill test. The percentage of apoptotic cells after the marathon changed in a biphasic manner. An early increase 3 h after the run was followed by a significant decrease 1 d later. Interestingly, the increase in apoptotic cells was not observed in highly trained athletes, whereas it was significantly more pronounced in badly trained athletes. ExT induced a lymphocyte apoptosis similar to the marathon, whereas no change in apoptosis was observed after the LoT. Both Fas receptor and ligand were increased after the marathon with different kinetics. Whereas the Fas receptor peaked at 1 h, Fas ligand was increased 3 h after the run. After the treadmill tests Fas receptor expression was enhanced in both groups, whereas Fas ligand increased only after the ExT. Endurance exercise like a marathon is able to induce apoptosis in lymphocytes. Thereby, apoptosis sensitivity seems to be related to training status in an inverse relationship. The increased expression levels of death receptors and ligands might indicate the high apoptosis inducing potential of this type of exercise.
Article
Doxorubicin (Dox) is a highly effective antineoplastic antibiotic associated with a dose-limiting cardiotoxicity that may result in irreversible cardiomyopathy and heart failure. The purpose of this study was to examine the effects of low-intensity exercise training (LIET) during the course of Dox treatment on cardiac function, myosin heavy chain expression, oxidative stress, and apoptosis activation following treatment. Male Sprague-Dawley rats either remained sedentary or were exercise trained on a motorized treadmill at 15 m/min, 20 min/day, 5 days/wk (Monday through Friday) for 2 wk. During the same 2-wk period, Dox (2.5 mg/kg) or saline was administered intraperitoneally to sedentary and exercised rats 3 days/wk (Monday, Wednesday, Friday) 1-2 h following the exercise training sessions (cumulative Dox dose: 15 mg/kg). Five days following the final injections, hearts were isolated for determination of left ventricular (LV) function, lipid peroxidation, antioxidant enzyme protein expression, 72-kDa heat shock protein expression, caspase-3 activity, and myosin heavy chain isoform expression. Dox treatment significantly impaired LV function and increased caspase-3 activity in sedentary animals (P < 0.05). LIET attenuated the LV dysfunction and apoptotic signal activation induced by Dox treatment and increased glutathione peroxidase expression, but it had no significant effect on lipid peroxidation, protein expression of myosin heavy chain isoforms, 72-kDa heat shock protein, or superoxide dismutase isoforms. In conclusion, our data suggest that LIET applied during chronic Dox treatment protects against cardiac dysfunction following treatment, possibly by enhancing antioxidant defenses and inhibiting apoptosis.
Article
Because lymphocyte apoptosis is significantly elevated immediately following high-intensity exercise in humans, it seems intuitive that the cell death process must be initiated at some point during the task. This study was designed to determine whether exercise-induced lymphocyte apoptosis occurs at a threshold level of intensity, or exists only following maximal or near-maximal exercise intensities. Fourteen untrained subjects completed a discontinuous, incremental treadmill test to exhaustion (.VO(2max)). Blood for films was sampled before the test, immediately after each work stage, and for 1-h postexercise. Blood smears were stained with May-Grünwald Giemsa and lymphocytes were evaluated for characteristic features of apoptosis. The apoptotic index (AI) during exercise at 38 % .VO(2max) was similar to pre-exercise but significantly elevated at an intensity approximating 61 % .VO(2max) (p < 0.0001). Significant increases in apoptosis were noted with additional elevations in exercise intensity (i.e., 76 %, 89 %, and 100 %, p < 0.0001). Following 20 min of recovery, AI was significantly lower than values obtained immediately postexercise (p < 0.0001). Forty minutes of recovery resulted in a further significant decrease (p < 0.0001), and by 1-h postexercise, AI was similar to pre-exercise values. Results indicate that the exercise intensity threshold for inducing an increase in lymphocyte apoptosis occurs between 40 and 60 % .VO(2max). In addition, since values return to baseline within 1 h following exhaustive exercise, it is unlikely that factors responsible for the apoptotic response in lymphocytes maintain a prolonged presence once exercise has been terminated.
Article
The clinical use of the chemotherapeutic drug doxorubicin (DOX) is limited due to a dose-dependent cardiotoxicity. Evidence is mounting that exercise protects against DOX-related cardiac dysfunction, and as such, it may be possible that prior endurance training promotes defense against DOX cardiotoxicity. To examine the effects of exercise preconditioning on acute DOX-induced cardiotoxicity, and to determine whether any observed cardioprotection was associated with myosin heavy chain (MHC) isoform alterations. Male Sprague-Dawley rats trained on a motorized treadmill, had access to voluntary running wheels, or remained sedentary for 10 wk prior to being injected with either saline or 10 mg.kg(-1) DOX. Left ventricular function was then assessed in vivo using transthoracic echocardiography and ex vivo using the isolated working heart at 5 and 10 d after injection. Additionally, left ventricular MHC isoform expression was analyzed as a possible mechanism to explain exercise-induced cardioprotection. DOX treatment promoted significant in vivo and ex vivo cardiac dysfunction at 5 and 10 d after injection in sedentary animals, and this dysfunction was associated with an upregulation of the beta-MHC isoform. Exercise preconditioning protected against DOX-induced cardiac dysfunction at 5 and 10 d after injection by attenuating beta-MHC upregulation. Endurance training prior to DOX treatment protects against acute DOX cardiotoxicity for up to 10 d, and this protection can potentially be explained by a preservation of MHC isoform distribution.
Exercise induced oxidative stress: DNA damage and expression of stress proteins in leucocytes—an overview
  • A Niess
  • S Veihelmann
  • F Passek
Niess A, Veihelmann S, Passek F, et al. Exercise induced oxidative stress: DNA damage and expression of stress proteins in leucocytes—an overview. Dtsch Z Sportmed. 1997;48:330-341.