| 1. |
- Rundqvist, Helene, et al.
(author)
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Activation of the erythropoietin receptor in human skeletal muscle
- 2009
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In: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 161:3, s. 427-434
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Journal article (peer-reviewed)abstract
- Objective: Erythropoietin receptor (EPOR) expression in non-hematological tissues has been shown to be activated by locally produced and/or systemically delivered EPO. Improved oxygen homeostasis, a well-established consequence of EPOR activation, is very important for human skeletal muscle performance. In the present study we investigate whether human skeletal muscle fibers and satellite cells express EPOR and if it is activated by exercise. Design and methods: Ten healthy males performed 65 min of cycle exercise. Biopsies were obtained from the vastus lateralis muscle and femoral arterio-venous differences in EPO concentrations were estimated. Results: The EPOR proteinwas localized in areas corresponding to the sarcolemma and capillaries. Laser dissection identified EPOR mRNA expression in muscle fibers. Also, EPOR mRNA and protein were both detected in human skeletal muscle satellite cells. In the initial part of the exercise bout there was a release of EPO from the exercising leg to the circulation, possibly corresponding to an increased bioavailability of EPO. After exercise, EPOR mRNA and EPOR-associated JAK2 phosphorylation were increased. Conclusions: Interaction with JAK2 is required for EPOR signaling and the increase found in phosphorylation is therefore closely linked to the activation of EPOR. The receptor activation by acute exercise suggests that signaling through EPOR is involved in exercise-induced skeletal muscle adaptation, thus extending the biological role of EPO into the skeletal muscle.
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| 2. |
- Ansund, Josefin, et al.
(author)
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High intensity exercise during breast cancer chemotherapy - effects on long-term myocardial damage and physical capacity - data from the OptiTrain RCT.
- 2021
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In: Cardio-oncology (London, England). - : Springer Science and Business Media LLC. - 2057-3804. ; 7:1, s. 7-
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Journal article (peer-reviewed)abstract
- BACKGROUND: Adjuvant systemic breast cancer treatment improves disease specific outcomes, but also presents with cardiac toxicity. In this post-hoc exploratory analysis of the OptiTrain trial, the effects of exercise on cardiotoxicity were monitored by assessing fitness and biomarkers over the intervention and into survivorship. Methods; Women starting chemotherapy were randomized to 16-weeks of resistance and high-intensity interval training (RT-HIIT), moderate-intensity aerobic and high-intensity interval training (AT-HIIT), or usual care (UC). Outcome measures included plasma troponin-T (cTnT), Nt-pro-BNP and peak oxygen uptake (VO2peak), assessed at baseline, post-intervention, and at 1- and 2-years.RESULTS: For this per-protocol analysis, 88 women met criteria for inclusion. Plasma cTnT increased in all groups post-intervention. At the 1-year follow-up, Nt-pro-BNP was lower in the exercise groups compared to UC. At 2-years there was a drop in VO2peak for patients with high cTnT and Nt-pro-BNP. Fewer patients in the RT-HIIT group fulfilled biomarker risk criteria compared to UC (OR 0.200; 95% CI = 0.055-0.734).CONCLUSIONS: In this cohort, high-intensity exercise was associated with lower levels of NT-proBNP 1-year post-baseline, but not with cTnT directly after treatment completion. This may, together with the preserved VO2peak in patients with low levels of biomarkers, indicate a long-term cardioprotective effect of exercise.TRIAL REGISTRATION: Clinicaltrials. govNCT02522260 , Registered 13th of august 2015 - Retrospectively Registered.
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| 3. |
- Bolam, Kate, et al.
(author)
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Association between change in cardiorespiratory fitness and prostate cancer incidence and mortality in 57 652 Swedish men.
- 2024
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In: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 58:7, s. 366-372
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To examine the associations between changes in cardiorespiratory fitness (CRF) in adulthood and prostate cancer incidence and mortality.METHODS: In this prospective study, men who completed an occupational health profile assessment including at least two valid submaximal CRF tests, performed on a cycle ergometer, were included in the study. Data on prostate cancer incidence and mortality were derived from national registers. HRs and CIs were calculated using Cox proportional hazard regression with inverse probability treatment weights of time-varying covariates.RESULTS: During a mean follow-up time of 6.7 years (SD 4.9), 592 (1%) of the 57 652 men were diagnosed with prostate cancer, and 46 (0.08%) died with prostate cancer as the primary cause of death. An increase in absolute CRF (as % of L/min) was associated with a reduced risk of prostate cancer incidence (HR 0.98, 95% CI 0.96 to 0.99) but not mortality, in the fully adjusted model. When participants were grouped as having increased (+3%), stable (±3%) or decreased (-3%) CRF, those with increased fitness also had a reduced risk of prostate cancer incidence compared with those with decreased fitness (HR 0.65, 95% CI 0.49 to 0.86), in the fully adjusted model.CONCLUSION: In this study of employed Swedish men, change in CRF was inversely associated with risk of prostate cancer incidence, but not mortality. Change in CRF appears to be important for reducing the risk of prostate cancer.
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| 4. |
- Bolam, Kate, et al.
(author)
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Two-year follow-up of the OptiTrain randomised controlled exercise trial.
- 2019
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In: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 175:3, s. 637-648
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Journal article (peer-reviewed)abstract
- PURPOSE: The aim of this study was to determine if there were any differences in health-related outcomes and physical activity (PA) between the two OptiTrain exercise groups and usual care (UC), 2 years post-baseline.METHODS: The OptiTrain study was a three-arm randomised controlled trial comparing 16 weeks of concurrent aerobic high-intensity interval training (HIIT) and progressive resistance exercise (RT-HIIT) or concurrent HIIT and continuous moderate-intensity aerobic exercise (AT-HIIT) to UC in 206 patients with breast cancer undergoing chemotherapy. Eligible participants were approached 2 years following baseline to assess cancer-related fatigue, quality of life, symptoms, muscle strength, cardiorespiratory fitness, body mass, PA, sedentary behaviour, and sick leave.RESULTS: The RT-HIIT group reported lower total cancer-related fatigue, (- 1.37, 95% CI - 2.70, - 0.04, ES = - 0.06) and cognitive cancer-related fatigue (- 1.47, 95% CI - 2.75, - 0.18, ES = - 0.28), and had higher lower limb muscle strength (12.09, 95% CI 3.77, 20.40, ES = 0.52) than UC at 2 years. The AT-HIIT group reported lower total symptoms (- 0.23, 95% CI - 0.42, - 0.03, ES = - 0.15), symptom burden (- 0.30, 95% CI - 0.60, - 0.01, ES = - 0.19), and body mass - 2.15 (- 3.71, - 0.60, ES = - 0.28) than UC at 2 years.CONCLUSION: At 2 years, the exercise groups were generally experiencing positive differences in cancer-related fatigue (RT-HIIT), symptoms (AT-HIIT), and muscle strength (RT-HIIT) to UC. The findings provide novel evidence that being involved in an exercise program during chemotherapy can have long-term benefits for women with breast cancer, but that strategies are needed to create better pathways to support patients to maintain physical activity levels.TRIAL REGISTRATION: Clinicaltrials.gov registration number: NCT02522260. Trial registered on 9 June 2015. https://clinicaltrials.gov/ct2/show/NCT02522260 . Retrospectively registered.
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| 5. |
- Ekblom Bak, Elin, 1981-, et al.
(author)
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Association Between Cardiorespiratory Fitness and Cancer Incidence and Cancer-Specific Mortality of Colon, Lung, and Prostate Cancer Among Swedish Men.
- 2023
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In: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 6:6
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Journal article (peer-reviewed)abstract
- IMPORTANCE: Cardiorespiratory fitness (CRF) levels appear to be an important risk factor for cancer incidence and death.OBJECTIVES: To examine CRF and prostate, colon, and lung cancer incidence and mortality in Swedish men, and to assess whether age moderated any associations between CRF and cancer.DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted in a population of men who completed an occupational health profile assessment between October 1982 and December 2019 in Sweden. Data analysis was performed from June 22, 2022, to May 11, 2023.EXPOSURE: Cardiorespiratory fitness was assessed as maximal oxygen consumption, estimated using a submaximal cycle ergometer test.MAIN OUTCOMES AND MEASURES: Data on prostate, colon, and lung cancer incidence and mortality were derived from national registers. Hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazards regression.RESULTS: Data on 177 709 men (age range, 18-75 years; mean [SD] age, 42 [11] years; mean [SD] body mass index, 26 [3.8]) were analyzed. During a mean (SD) follow-up time of 9.6 (5.5) years, a total of 499 incident cases of colon, 283 of lung, and 1918 of prostate cancer occurred, as well as 152 deaths due to colon cancer, 207 due to lung cancer, and 141 deaths due to prostate cancer. Higher levels of CRF (maximal oxygen consumption as milliliters per minute per kilogram) were associated with a significantly lower risk of colon (HR, 0.98, 95% CI, 0.96-0.98) and lung cancer (HR, 0.98; 95% CI, 0.96-0.99) incidence, and a higher risk of prostate cancer incidence (HR, 1.01; 95% CI, 1.00-1.01). Higher CRF was associated with a lower risk of death due to colon (HR, 0.98; 95% CI, 0.96-1.00), lung (HR, 0.97; 95% CI, 0.95-0.99), and prostate (HR, 0.95; 95% CI, 0.93-0.97) cancer. After stratification into 4 groups and in fully adjusted models, the associations remained for moderate (>35-45 mL/min/kg), 0.72 (0.53-0.96) and high (>45 mL/min/kg), 0.63 (0.41-0.98) levels of CRF, compared with very low (<25 mL/min/kg) CRF for colon cancer incidence. For prostate cancer mortality, associations remained for low (HR, 0.67; 95% CI, 0.45-1.00), moderate (HR, 0.57; 95% CI, 0.34-0.97), and high (HR, 0.29; 95% CI, 0.10-0.86) CRF. For lung cancer mortality, only high CRF (HR, 0.41; 95% CI, 0.17-0.99) was significant. Age modified the associations for lung (HR, 0.99; 95% CI, 0.99-0.99) and prostate (HR, 1.00; 95% CI, 1.00-1.00; P < .001) cancer incidence, and for death due to lung cancer (HR, 0.99; 95% CI, 0.99-0.99; P = .04).CONCLUSIONS AND RELEVANCE: In this cohort of Swedish men, moderate and high CRF were associated with a lower risk of colon cancer. Low, moderate, and high CRF were associated with lower risk of death due to prostate cancer, while only high CRF was associated with lower risk of death due to lung cancer. If evidence for causality is established, interventions to improve CRF in individuals with low CRF should be prioritized.
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| 6. |
- Evans, Colin E, et al.
(author)
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Modelling pulmonary microthrombosis coupled to metastasis : Distinct effects of thrombogenesis on tumorigenesis
- 2017
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In: Biology Open. - : The Company of Biologists. - 2046-6390. ; 6:5, s. 688-697
-
Journal article (peer-reviewed)abstract
- Thrombosis can cause localized ischemia and tissue hypoxia, and both of these are linked to cancer metastasis. Vascular microocclusion can occur as a result of arrest of circulating tumour cells in small capillaries, giving rise to microthrombotic events that affect flow, creating localized hypoxic regions. To better understand the association between metastasis and thrombotic events, we generated an experimental strategy whereby we modelled the effect of microvascular occlusion in metastatic efficiency by using inert microbeads to obstruct lung microvasculature before, during and after intravenous tumour cell injection.We found that controlled induction of a specific number of these microthrombotic insults in the lungs caused an increase in expression of the hypoxia-inducible transcription factors (HIFs), a pro-Angiogenic and pro-Tumorigenic environment, as well as an increase in myeloid cell infiltration. Induction of pulmonary microthrombosis prior to introduction of tumour cells to the lungs had no effect on tumorigenic success, but thrombosis at the time of tumour cell seeding increased number and size of tumours in the lung, and this effect was strikingly more pronounced when the microocclusion occurred on the day following introduction of tumour cells. The tumorigenic effect of microbead treatment was seen even when thrombosis was induced five days after tumour cell injection. We also found positive correlations between thrombotic factors and expression of HIF2α in human tumours. The model system described here demonstrates the importance of thrombotic insult in metastatic success and can be used to improve understanding of thrombosis-Associated tumorigenesis and its treatment.
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| 7. |
- Hiensch, Anouk E, et al.
(author)
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Design of a multinational randomized controlled trial to assess the effects of structured and individualized exercise in patients with metastatic breast cancer on fatigue and quality of life : the EFFECT study.
- 2022
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In: Trials. - : Springer Science and Business Media LLC. - 1745-6215. ; 23:1, s. 610-
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Journal article (peer-reviewed)abstract
- BACKGROUND: Many patients with metastatic breast cancer experience cancer- and treatment-related side effects that impair activities of daily living and negatively affect the quality of life. There is a need for interventions that improve quality of life by alleviating fatigue and other side effects during palliative cancer treatment. Beneficial effects of exercise have been observed in the curative setting, but, to date, comparable evidence in patients with metastatic breast cancer is lacking. The aim of this study is to assess the effects of a structured and individualized 9-month exercise intervention in patients with metastatic breast cancer on quality of life, fatigue, and other cancer- and treatment-related side effects.METHODS: The EFFECT study is a multinational, randomized controlled trial including 350 patients with metastatic breast cancer. Participants are randomly allocated (1:1) to an exercise or control group. The exercise group participates in a 9-month multimodal exercise program, starting with a 6-month period where participants exercise twice a week under the supervision of an exercise professional. After completing this 6-month period, one supervised session is replaced by one unsupervised session for 3 months. In addition, participants are instructed to be physically active for ≥30 min/day on all remaining days of the week, while being supported by an activity tracker and exercise app. Participants allocated to the control group receive standard medical care, general written physical activity advice, and an activity tracker, but no structured exercise program. The primary outcomes are quality of life (EORTC QLQ-C30, summary score) and fatigue (EORTC QLQ-FA12), assessed at baseline, 3, 6 (primary endpoint), and 9 months post-baseline. Secondary outcomes include physical fitness, physical performance, physical activity, anxiety, depression, pain, sleep problems, anthropometric data, body composition, and blood markers. Exploratory outcomes include quality of working life, muscle thickness, urinary incontinence, disease progression, and survival. Additionally, the cost-effectiveness of the exercise program is assessed. Adherence and safety are monitored throughout the intervention period.DISCUSSION: This large randomized controlled trial will provide evidence regarding the (cost-) effectiveness of exercise during treatment of metastatic breast cancer. If proven (cost-)effective, exercise should be offered to patients with metastatic breast cancer as part of standard care.TRIAL REGISTRATION: ClinicalTrials.gov NCT04120298 . Registered on October 9, 2019.
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| 8. |
- Hiensch, Anouk E, et al.
(author)
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Doxorubicin-induced skeletal muscle atrophy : Elucidating the underlying molecular pathways.
- 2020
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In: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 229:2
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Journal article (peer-reviewed)abstract
- AIM: Loss of skeletal muscle mass is a common clinical finding in cancer patients. The purpose of this meta-analysis and systematic review was to quantify the effect of doxorubicin on skeletal muscle and report on the proposed molecular pathways possibly leading to doxorubicin-induced muscle atrophy in both human and animal models.METHODS: A systematic search of the literature was conducted in PubMed, EMBASE, Web of Science and CENTRAL databases. The internal validity of included studies was assessed using SYRCLE's risk of bias tool.RESULTS: Twenty eligible articles were identified. No human studies were identified as being eligible for inclusion. Doxorubicin significantly reduced skeletal muscle weight (ie EDL, TA, gastrocnemius and soleus) by 14% (95% CI: 9.9; 19.3) and muscle fibre cross-sectional area by 17% (95% CI: 9.0; 26.0) when compared to vehicle controls. Parallel to negative changes in muscle mass, muscle strength was even more decreased in response to doxorubicin administration. This review suggests that mitochondrial dysfunction plays a central role in doxorubicin-induced skeletal muscle atrophy. The increased production of ROS plays a key role within this process. Furthermore, doxorubicin activated all major proteolytic systems (ie calpains, the ubiquitin-proteasome pathway and autophagy) in the skeletal muscle. Although each of these proteolytic pathways contributes to doxorubicin-induced muscle atrophy, the activation of the ubiquitin-proteasome pathway is hypothesized to play a key role. Finally, a limited number of studies found that doxorubicin decreases protein synthesis by a disruption in the insulin signalling pathway.CONCLUSION: The results of the meta-analysis show that doxorubicin induces skeletal muscle atrophy in preclinical models. This effect may be explained by various interacting molecular pathways. Results from preclinical studies provide a robust setting to investigate a possible dose-response, separate the effects of doxorubicin from tumour-induced atrophy and to examine underlying molecular pathways. More research is needed to confirm the proposed signalling pathways in humans, paving the way for potential therapeutic approaches.
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| 9. |
- Koivula, Tiia, et al.
(author)
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The effect of acute exercise on circulating immune cells in newly diagnosed breast cancer patients
- 2023
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In: Scientific Reports. - London : Nature Publishing Group. - 2045-2322. ; 13:1
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Journal article (peer-reviewed)abstract
- The role of exercise in cancer prevention and control is increasingly recognized, and based on preclinical studies, it is hypothesized that mobilization of leukocytes plays an important role in the anti-tumor effect. Thus, we examined how 10-min acute exercise modulates immune cells in newly diagnosed breast cancer patients. Blood samples were taken at rest, immediately after exercise and 30 min after exercise and phenotypic characterization of major leukocyte subsets was done using 9-color flow cytometry. Total leukocyte count increased by 29%, CD8+ T cell count by 34%, CD19+ B cell count by 18%, CD56+CD16+ NK cell count by 130%, and CD14+CD16+ monocyte count by 51% immediately after acute exercise. Mobilization of CD45+, CD8+, CD19+, and CD56+CD16+ cells correlated positively with exercising systolic blood pressure, heart rate percentage of age predicted maximal heart rate, rate pressure product, and mean arterial pressure. Our findings indicate that a single bout of acute exercise of only 10 min can cause leukocytosis in breast cancer patients. Mobilization of leukocytes appear to be directly related to the intensity of exercise. It is possible that the positive effect of exercise on oncologic outcome might be partly due to immune cell mobilization as documented in the present study. © 2023, The Author(s).
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| 10. |
- Lanner, Johanna, et al.
(author)
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Running reverses tumor-induced muscle weakness in mice with breast cancer
- 2019
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Conference paper (peer-reviewed)abstract
- Introduction: Patients with breast cancer experience muscle dysfunction, which is a clinical challenge that is not restricted to advanced stage patients, but also observed in newly diagnosed weight-stable patients with low tumor burden. Recent data indicate that physical activity can reduce breast cancerassociated mortality, suggesting that improved muscle performance per secan have positive impact on survival. Here, the transgenic PyMT mouse model of breast cancer was used to elucidate molecular mechanisms underlying breast cancer-induced muscle impairments.Materials and Methods: PyMT mice and wildtype (WT) littermates w/wo access to an in-cage running wheel for four weeks (week 8-12). Functional readouts included Ca2+imaging; isometric force measurement on single fibers and intact fast-and slow-twitchmuscles. Intramuscular signaling was assessed using immunofluorescence, immunoblotting and enzymatic assays.Results: The specific force (i.e. force/cross-sectional area) was significantly decreased by ~ 35% in slow-twitch soleus muscles from breast cancermice as compared to WT muscles, which was the result of reduced Ca2+release and impaired myofibrillar function. There were no difference in muscle size or fiber type between the two groups. However, higher intramuscular stress (e.g. p38 activation and carbonylation (DNP)) was observed in PyMT than in WT. Intriguingly, voluntary running for four weeks reversed the weakness and PyMT soleus muscles generated similar forces as muscles of exercised WT mice. The running induced higher SOD2 expression and normalized levels of p38 and DNP.Conclusion: Intrinsic contractile dysfunction and higher intramuscular stress was present in mice with breast cancer, which was counteracted with voluntary running.
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| 11. |
- Mader, Theresa, et al.
(author)
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Exercise reduces intramuscular stress and counteracts muscle weakness in mice with breast cancer
- 2022
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In: Journal of Cachexia, Sarcopenia and Muscle. - : John Wiley & Sons. - 2190-5991 .- 2190-6009. ; 13:2, s. 1151-1163
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Journal article (peer-reviewed)abstract
- BACKGROUND: Patients with breast cancer exhibit muscle weakness, which is associated with increased mortality risk and reduced quality of life. Muscle weakness is experienced even in the absence of loss of muscle mass in breast cancer patients, indicating intrinsic muscle dysfunction. Physical activity is correlated with reduced cancer mortality and disease recurrence. However, the molecular processes underlying breast cancer-induced muscle weakness and the beneficial effect of exercise are largely unknown.METHODS: Eight-week-old breast cancer (MMTV-PyMT, PyMT) and control (WT) mice had access to active or inactive in-cage voluntary running wheels for 4 weeks. Mice were also subjected to a treadmill test. Muscle force was measured ex vivo. Tumour markers were determined with immunohistochemistry. Mitochondrial biogenesis and function were assessed with transcriptional analyses of PGC-1α, the electron transport chain (ETC) and antioxidants superoxide dismutase (Sod) and catalase (Cat), combined with activity measurements of SOD, citrate synthase (CS) and β-hydroxyacyl-CoA-dehydrogenase (βHAD). Serum and intramuscular stress levels were evaluated by enzymatic assays, immunoblotting, and transcriptional analyses of, for example, tumour necrosis factor-α (TNF-α) and p38 mitogen-activated protein kinase (MAPK) signalling.RESULTS: PyMT mice endured shorter time and distance during the treadmill test (~30%, P < 0.05) and ex vivo force measurements revealed ~25% weaker slow-twitch soleus muscle (P < 0.001). This was independent of cancer-induced alteration of muscle size or fibre type. Inflammatory stressors in serum and muscle, including TNF-α and p38 MAPK, were higher in PyMT than in WT mice (P < 0.05). Cancer-induced decreases in ETC (P < 0.05, P < 0.01) and antioxidant gene expression were observed (P < 0.05). The exercise intervention counteracted the cancer-induced muscle weakness and was accompanied by a less aggressive, differentiated tumour phenotype, determined by increased CK8 and reduced CK14 expression (P < 0.05). In PyMT mice, the exercise intervention led to higher CS activity (P = 0.23), enhanced β-HAD and SOD activities (P < 0.05), and reduced levels of intramuscular stressors together with a normalization of the expression signature of TNFα-targets and ETC genes (P < 0.05, P < 0.01). At the same time, the exercise-induced PGC-1α expression, and CS and β-HAD activity was blunted in muscle from the PyMT mice as compared with WT mice, indicative that breast cancer interfere with transcriptional programming of mitochondria and that the molecular adaptation to exercise differs between healthy mice and those afflicted by disease.CONCLUSIONS: Four-week voluntary wheel running counteracted muscle weakness in PyMT mice which was accompanied by reduced intrinsic stress and improved mitochondrial and antioxidant profiles and activities that aligned with muscles of healthy mice.
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| 12. |
- Mijwel, Sara, et al.
(author)
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Adding high-intensity interval training to conventional training modalities : optimizing health-related outcomes during chemotherapy for breast cancer: the OptiTrain randomized controlled trial
- 2018
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In: Breast Cancer Research and Treatment. - : Springer. - 0167-6806 .- 1573-7217. ; 168:1, s. 79-93
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Journal article (peer-reviewed)abstract
- PURPOSE: Exercise training is an effective and safe way to counteract cancer-related fatigue (CRF) and to improve health-related quality of life (HRQoL). High-intensity interval training has proven beneficial for the health of clinical populations. The aim of this randomized controlled trial was to compare the effects of resistance and high-intensity interval training (RT-HIIT), and moderate-intensity aerobic and high-intensity interval training (AT-HIIT) to usual care (UC) in women with breast cancer undergoing chemotherapy. The primary endpoint was CRF and the secondary endpoints were HRQoL and cancer treatment-related symptoms.METHODS: Two hundred and forty women planned to undergo chemotherapy were randomized to supervised RT-HIIT, AT-HIIT, or UC. Measurements were performed at baseline and at 16 weeks. Questionnaires included Piper Fatigue Scale, EORTC-QLQ-C30, and Memorial Symptom Assessment Scale.RESULTS: The RT-HIIT group was superior to UC for CRF: total CRF (p = 0.02), behavior/daily life (p = 0.01), and sensory/physical (p = 0.03) CRF. Role functioning significantly improved while cognitive functioning was unchanged for RT-HIIT compared to declines shown in the UC group (p = 0.04). AT-HIIT significantly improved emotional functioning versus UC (p = 0.01) and was superior to UC for pain symptoms (p = 0.03). RT-HIIT reported a reduced symptom burden, while AT-HIIT remained stable compared to deteriorations shown by UC (p < 0.01). Only RT-HIIT was superior to UC for total symptoms (p < 0.01).CONCLUSIONS: 16 weeks of resistance and HIIT was effective in preventing increases in CRF and in reducing symptom burden for patients during chemotherapy for breast cancer. These findings add to a growing body of evidence supporting the inclusion of structured exercise prescriptions, including HIIT, as a vital component of cancer rehabilitation.TRIAL REGISTRATION: Clinicaltrials.gov Registration Number: NCT02522260.
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| 13. |
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| 14. |
- Mijwel, Sara, et al.
(author)
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Effects of Exercise on Chemotherapy Completion and Hospitalization Rates : The OptiTrain Breast Cancer Trial.
- 2020
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In: The Oncologist. - : Oxford University Press (OUP). - 1083-7159 .- 1549-490X. ; 25:1, s. 23-32
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Journal article (peer-reviewed)abstract
- BACKGROUND: Exercise during chemotherapy is suggested to provide clinical benefits, including improved chemotherapy completion. Despite this, few randomized controlled exercise trials have reported on such clinical endpoints. From the OptiTrain trial we previously showed positive effects on physiological and health-related outcomes after 16 weeks of supervised exercise in patients with breast cancer undergoing chemotherapy. Here, we examined the effects of exercise on rates of chemotherapy completion and hospitalization, as well as on blood cell concentrations during chemotherapy.PATIENTS AND METHODS: Two hundred forty women scheduled for chemotherapy were randomized to 16 weeks of resistance and high-intensity interval training (RT-HIIT), moderate-intensity aerobic and high-intensity interval training (AT-HIIT), or usual care (UC). Outcomes included chemotherapy completion, hospitalization, hemoglobin, lymphocyte, thrombocyte, and neutrophil concentrations during chemotherapy.RESULTS: No significant between-groups differences were found in the proportion of participants who required dose reductions (RT-HIIT vs. UC: odds ratio [OR], 1.08; AT-HIIT vs. UC: OR, 1.39), or average relative dose intensity of chemotherapy between groups (RT-HIIT vs. UC: effect size [ES], 0.08; AT-HIIT vs. UC: ES, -0.07). A significantly lower proportion of participants in the RT-HIIT group (3%) were hospitalized during chemotherapy compared with UC (15%; OR, 0.20). A significantly lower incidence of thrombocytopenia was found for both RT-HIIT (11%) and AT-HIIT (10%) versus UC (30%; OR, 0.27; OR, 0.27).CONCLUSION: No beneficial effects of either RT-HIIT or AT-HIIT on chemotherapy completion rates were found. However, combined resistance training and high-intensity interval training were effective to reduce hospitalization rates, and both exercise groups had a positive effect on thrombocytopenia. These are important findings with potential positive implications for the health of women with breast cancer and costs associated with treatment-related complications.IMPLICATIONS FOR PRACTICE: Completing the prescribed chemotherapy regimen is strongly associated with a good prognosis for patients with primary breast cancer. Despite this, treatment-induced side effects make it necessary to reduce or alter the treatment regimen and can also lead to hospitalization. Exercise during chemotherapy is suggested to provide clinical benefits, including improved chemotherapy completion. This study showed that combined resistance and high-intensity interval training during chemotherapy resulted in lower hospitalization rates and a lower incidence of thrombocytopenia in women with breast cancer undergoing chemotherapy. However, no beneficial effects of either exercise program on chemotherapy completion rates were found, which is in contrast to previous findings in this population. The findings reported in the current article have positive implications for the health of women with breast cancer and costs associated with treatment-related complications.
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| 15. |
- Mijwel, Sara, et al.
(author)
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Exercise training during chemotherapy preserves skeletal muscle fiber area, capillarization, and mitochondrial content in patients with breast cancer.
- 2018
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In: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 32:10, s. 5495-5505
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Journal article (peer-reviewed)abstract
- Exercise has been suggested to ameliorate the detrimental effects of chemotherapy on skeletal muscle. The aim of this study was to compare the effects of different exercise regimens with usual care on skeletal muscle morphology and mitochondrial markers in patients being treated with chemotherapy for breast cancer. Specifically, we compared moderate-intensity aerobic training combined with high-intensity interval training (AT-HIIT) and resistance training combined with high-intensity interval training (RT-HIIT) with usual care (UC). Resting skeletal muscle biopsies were obtained pre- and postintervention from 23 randomly selected women from the OptiTrain breast cancer trial who underwent RT-HIIT, AT-HIIT, or UC for 16 wk. Over the intervention, citrate synthase activity, muscle fiber cross-sectional area, capillaries per fiber, and myosin heavy chain isoform type I were reduced in UC, whereas RT-HIIT and AT-HIIT were able to counteract these declines. AT-HIIT promoted up-regulation of the electron transport chain protein levels vs. UC. RT-HIIT favored satellite cell count vs. UC and AT-HIIT. There was a significant association between change in citrate synthase activity and self-reported fatigue. AT-HIIT and RT-HIIT maintained or improved markers of skeletal muscle function compared with the declines found in the UC group, indicating a sustained trainability in addition to the preservation of skeletal muscle structural and metabolic characteristics during chemotherapy. These findings highlight the importance of supervised exercise programs for patients with breast cancer during chemotherapy.-Mijwel, S., Cardinale, D. A., Norrbom, J., Chapman, M., Ivarsson, N., Wengström, Y., Sundberg, C. J., Rundqvist, H. Exercise training during chemotherapy preserves skeletal muscle fiber area, capillarization, and mitochondrial content in patients with breast cancer.
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| 16. |
- Mijwel, Sara, et al.
(author)
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High-intensity exercise during chemotherapy induces beneficial effects 12 months into breast cancer survivorship.
- 2019
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In: Journal of cancer survivorship. - : Springer Science and Business Media LLC. - 1932-2259 .- 1932-2267. ; 13:2, s. 244-256
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Journal article (peer-reviewed)abstract
- PURPOSE: Whether the benefits of exercise during chemotherapy continue into survivorship is not well-known. Here, the aim was to examine the effects of two exercise interventions on self-reported health-related and objectively measured physiological outcomes 12 months following commencement of chemotherapy.METHODS: Two hundred and forty women with breast cancer stage I-IIIa were randomized to 16 weeks of high-intensity aerobic interval training combined with either resistance training (RT-HIIT), or moderate-intensity aerobic training (AT-HIIT), or to usual care (UC).PRIMARY OUTCOME: cancer-related fatigue (CRF); secondary outcomes: quality of life (QoL), symptom burden, muscle strength, cardiorespiratory-fitness, body mass, and return to work.RESULTS: Compared to UC, both RT-HIIT and AT-HIIT significantly counteracted increases in total CRF (ES = - 0.34; ES = - 0.10), daily life CRF (ES=-0.76; ES=-0.50, and affective CRF (ES=-0.60; ES=-0.39). Both RT-HIIT and AT-HIIT reported significantly lower total symptoms (ES = - 0.46, ES = - 0.46), and displayed gains in lower limb (ES = 0.73; ES = 1.03) and handgrip muscle strength (surgery side ES = 0.70, ES = 0.71; non-surgery side ES = 0.57, ES = 0.59). AT-HIIT displayed significant reductions in body mass (ES = - 0.24), improved QoL: role (ES = 0.33) and emotional functioning (ES = 0.40), and a larger proportion had returned to work (p = 0.02) vs UC.CONCLUSION: These findings emphasize the beneficial effects of supervised high-intensity exercise during chemotherapy to improve the health and to reduce societal costs associated with prolonged sick leave for patients with breast cancer several months following chemotherapy.IMPLICATIONS FOR CANCER SURVIVORS: These findings provide important information with substantial positive consequences for breast cancer survivorship. High-intensity exercise programs during chemotherapy and support to maintain physical activity can be a powerful strategy to manage or prevent many of the short- and long-term adverse effects of treatment for the increasing cohort of cancer survivors.
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| 17. |
- Mijwel, Sara, et al.
(author)
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Highly favorable physiological responses to concurrent resistance and high-intensity interval training during chemotherapy : the OptiTrain breast cancer trial.
- 2018
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In: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 169:1, s. 93-103
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Journal article (peer-reviewed)abstract
- BACKGROUND: Advanced therapeutic strategies are often accompanied by significant adverse effects, which warrant equally progressive countermeasures. Physical exercise has proven an effective intervention to improve physical function and reduce fatigue in patients undergoing chemotherapy. Effects of high-intensity interval training (HIIT) in this population are not well established although HIIT has proven effective in other clinical populations. The aim of the OptiTrain trial was to examine the effects of concurrent resistance and high-intensity interval training (RT-HIIT) or concurrent moderate-intensity aerobic and high-intensity interval training (AT-HIIT), to usual care (UC) on pain sensitivity and physiological outcomes in patients with breast cancer during chemotherapy.METHODS: Two hundred and forty women were randomized to 16 weeks of RT-HIIT, AT-HIIT, or UC.OUTCOMES: cardiorespiratory fitness, muscle strength, body mass, hemoglobin levels, and pressure-pain threshold.RESULTS: Pre- to post-intervention, RT-HIIT (ES = 0.41) and AT-HIIT (ES = 0.42) prevented the reduced cardiorespiratory fitness found with UC. Handgrip strength (surgery side: RT-HIIT vs. UC: ES = 0.41, RT-HIIT vs. AT-HIIT: ES = 0.28; non-surgery side: RT-HIIT vs. UC: ES = 0.35, RT-HIIT vs. AT-HIIT: ES = 0.22) and lower-limb muscle strength (RT-HIIT vs. UC: ES = 0.66, RT-HIIT vs. AT-HIIT: ES = 0.23) were significantly improved in the RT-HIIT. Increases in body mass were smaller in RT-HIIT (ES = - 0.16) and AT-HIIT (ES = - 0.16) versus UC. RT-HIIT reported higher pressure-pain thresholds than UC (trapezius: ES = 0.46, gluteus: ES = 0.53) and AT-HIIT (trapezius: ES = 0.30).CONCLUSION: Sixteen weeks of RT-HIIT significantly improved muscle strength and reduced pain sensitivity. Both exercise programs were well tolerated and were equally efficient in preventing increases in body mass and in preventing declines in cardiorespiratory fitness. These results highlight the importance of implementing a combination of resistance and high-intensity interval training during chemotherapy for women with breast cancer.
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| 18. |
- Mijwel, Sara, et al.
(author)
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Validation of 2 Submaximal Cardiorespiratory Fitness Tests in Patients With Breast Cancer Undergoing Chemotherapy.
- 2016
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In: Rehabilitation oncology (American Physical Therapy Association. Oncology Section). - 2168-3808. ; 34:4, s. 137-143
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Journal article (peer-reviewed)abstract
- Patients with breast cancer have an impaired cardiorespiratory fitness, in part, due to the toxic effects of anticancer therapy. Physical exercise as a means of rehabilitation for patients with cancer is an emerging area of research and treatment, emphasizing the need for accurate and feasible physical capacity measurements. The purpose of this study was to evaluate the validity of peak oxygen consumption (o2peak) predicted by the Ekblom-Bak test (E-B) and the Åstrand-Rhyming prediction model (A-R).METHODS: Eight patients with breast cancer undergoing chemotherapy participated in the study. Submaximal exercise tests were performed at 2 different submaximal workloads. Estimated o2peak values were obtained by inserting the heart rate (HR) from the 2 workloads into the E-B prediction model and the HR of only the higher workload into the Åstrand nomogram. A 20-W incremental cycle test-to-peak effort was performed to obtain o2peak values.RESULTS: Results from A-R overestimated o2peak by 6% (coefficient of variation = 7%), whereas results from E-B overestimated o2peak with 42% (coefficient of variation = 21%) compared with measured o2peak. Pearson's correlation coefficient revealed a significant strong relationship between the estimated o2peak from A-R and the measured o2peak (r = 0.86; P < .05), whereas the relationship between the estimated o2peak from E-B and the measured o2peak resulted in a nonsignificant weak correlation (r = 0.21).CONCLUSION: In a situation where maximal exercise testing is not practical or undesirable from a patient safety perspective, submaximal exercise testing provides an alternative way of estimating o2peak. The A-R prediction model appears to be a valid submaximal exercise test for determining cardiorespiratory fitness in this population.
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| 19. |
- Palazon, Asis, et al.
(author)
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An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression
- 2017
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In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 32:5, s. 5-683
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Journal article (peer-reviewed)abstract
- Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1α, but not HIF-2α, was essential for the effector state in CD8+ T cells. Furthermore, loss of HIF-1α in CD8+ T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization. Deletion of VEGF-A, an HIF target gene, in CD8+ T cells accelerated tumorigenesis while also altering vascularization. Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8+ T cell infiltration, and a link between T cell infiltration and vascularization. These data demonstrate that the HIF-1α/VEGF-A axis is an essential aspect of tumor immunity. Palazon et al. demonstrate the importance of the HIF-1α/VEGF-A axis in tumor immunity. HIF-1α, but not HIF-2α, drives CD8+ T cell glycolytic metabolism, migration, and effector function, while the HIF-1α transcriptional target VEGF-A contributes to tumor vascularization.
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| 20. |
- Rullman, Eric, et al.
(author)
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Endurance exercise activates matrix metalloproteinases in human skeletal muscle
- 2009
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In: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 106:3, s. 804-812
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Journal article (peer-reviewed)abstract
- In the present study, the effect of exercise training on the expression and activity of matrix metalloproteinases (MMPs) in the human skeletal muscle was investigated. Ten subjects exercised one leg for 45 min with restricted blood flow and then exercised the other leg at the same absolute workload with unrestricted blood flow. The exercises were conducted four times per week for 5 wk. Biopsies were taken from the vastus lateralis muscles of both legs at rest before the training period, after 10 days and 5 wk of training, and 2 h after the first exercise bout for analysis of MMP and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA, enzyme activity, and protein expression. Levels of MMP-2, MMP-14, and TIMP-1 mRNA in muscle tissue increased after 10 days of training regardless of blood flow condition. MMP-2 mRNA level in laser-dissected myofibers and MMP-2 activity in whole muscle increased with training. The level of MMP-9 mRNA and activity increased after the first bout of exercise. Although MMP-9 mRNA levels appeared to be very low, the activity of MMP-9 after a single bout of exercise was similar to that of MMP-2 after 10 days of exercise. MMP-2 and MMP-9 protein was both present throughout the extracellular matrix of the muscle, both around fibers and capillaries, but MMP-2 was also present within the skeletal muscle fibers. These results show that MMPs are activated in skeletal muscle in nonpathological conditions such as voluntary exercise. The expression and time pattern indicate differences between the MMPs in regards of production sites as well as in the regulating mechanism
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| 21. |
- Rundqvist, Helene, et al.
(author)
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[Physical activity supports cardiovascular fitness and muscle strength and has positive effects on quality of life among cancer survivors]. : Rekommendation om träning vid cancer kan förbättra livskvalitet.
- 2022
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In: Läkartidningen. - 0023-7205. ; 119
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Journal article (peer-reviewed)abstract
- Enhanced screening and efficient cancer treatments have led to a growing number of cancer survivors. In Sweden over 500 000 individuals have or have had cancer [1]. Cancer survivors can experience a wide range of disease and treatment related symptoms, that profoundly affect their health related quality of life. For example, women treated for breast cancer have on average 25 percent lower physical fitness compared to women without a cancer diagnosis. Recent evidence suggests that exercise has a positive effect on physical fitness, muscle strength, cancer related fatigue and quality of life among cancer survivors. An effective exercise prescription for health related outcomes in adult cancer survivors includes aerobic training at a moderate intensity for a total of 150 minutes per week. Adding resistance training two times per week has additional effects on muscle strength and physical functioning. Supervised exercise programs seem to be more effective than unsupervised or home based programs.
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| 22. |
- Rundqvist, Helene
(author)
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Skeletal muscle HIF-1 and exercise
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Regular physical activity prevents and improves a number of disease conditions and reduces the risk for premature death substantially. From a clinical as well as a basic science point of view it is important to create a more fundamental understanding of the molecular mechanisms that contribute to the improved functional capacity induced by regular physical activity. Skeletal muscle tissue exhibits a remarkable ability to adapt to altered demands. Training adaptations include increased capillarisation, altered glycolytic flux and increased mitochondrial density and occur in response to repeated bouts of exercise. Skeletal muscle hypoxia has been addressed as one possible primary stimulus for adaptation to training. Hypoxia Inducible Factor-1 (HIF-1) has been suggested to be a master regulator of hypoxic transcription. Out of the HIF-1 regulated factors, several are known to be affected by exercise or associated with processes important for exercise adaptation e.g. Vascular Endothelial Growth Factor (VEGF), involved in exercise induced angiogenesis. Therefore, the principal aim of the thesis was to investigate a possible activation of and role for HIF-1 in skeletal muscle adaptation to exercise. Skeletal muscle biopsies were obtained from m. vastus lateralis in three human experimental set-ups; a single bout of exercise (Papers I and III), four weeks of endurance training (V) and elite athletes (V). In addition, two different mouse models were used, skeletal muscle specific HIF-1α KO mice exposed to six weeks of endurance training (IV) and electrically induced contractions in isolated mouse EDL and Soleus muscle (II). A single bout of exercise activated HIF-1, including protein stabilization, translocation to the nucleus, increased binding to target gene promoters and increased target gene expression (e.g. VEGF and VEGFR1) in both human and mouse skeletal muscle (I-III). However, the HIF-1α KO mice showed several of the features typically associated with a trained muscle, especially in respect of mitochondrial characteristics. This was suggested to at least in part be due to reduced activity of the HIF-1 inducible inhibitor of pyruvate dehydrogenase, pyruvate dehydrogense kinase 1 (PDK1). Recent studies suggest that the acute activation of HIF-1 target genes may be blunted after a period of exercise training. In Paper V it was hypothesized that a possible training induced moderation of HIF-1 activity would be reflected in skeletal muscle PDK1 levels. The results showed that PDK1 levels were significantly lower in elite athletes compared to moderately active individuals. Furthermore, a possible mechanism for moderating HIF-1 activity in response to endurance training was introduced. HIF-1 stability is known to be regulated by hydroxylation of critical proline residues by prolyl hydroxylase 1-3 (PHD1-3) with consequent proteasomal degradation. PHD2 had the highest expression of the three prolyl hydroxylases in human skeletal muscle and PHD2 levels were increased by training and higher in the elite trained athletes. Evidence of a regulatory link between PHD activity and PDK1 levels in human skeletal muscle was provided by inhibiting PHD activity in human primary myoblasts, resulting in increased PDK1 levels (V). From the results of Papers I-V it was proposed that an initial activation of HIF-1 may drive angiogenesis adaptation in the early phase of training, but the seeming attenuation of the HIF-1 response later in a training period may represent a switch toward a higher capacity to activate the oxidative system.
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| 23. |
- Siebenmann, Christoph, et al.
(author)
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Cutaneous exposure to hypoxia does not affect skin perfusion in humans
- 2017
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In: Acta Physiologica. - : Wiley-Blackwell. - 1748-1708 .- 1748-1716. ; 220:3, s. 361-369
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Journal article (peer-reviewed)abstract
- Aim: Experiments have indicated that skin perfusion in mice is sensitive to reductions in environmental O-2 availability. Specifically, a reduction in skin-surface PO2 attenuates transcutaneous O-2 diffusion, and hence epidermal O-2 supply. In response, epidermal HIF-1 alpha expression increases and facilitates initial cutaneous vasoconstriction and subsequent nitric oxide-dependent vasodilation. Here, we investigated whether the same mechanism exists in humans. Methods: In a first experiment, eight males rested twice for 8 h in a hypobaric chamber. Once, barometric pressure was reduced by 50%, while systemic oxygenation was preserved by O-2-enriched (42%) breathing gas (Hypoxia(Skin)), and once barometric pressure and inspired O-2 fraction were normal (Control(1)). In a second experiment, nine males rested for 8 h with both forearms wrapped in plastic bags. O-2 was expelled from one bag by nitrogen flushing (Anoxia(Skin)), whereas the other bag was flushed with air (Control(2)). In both experiments, skin blood flux was assessed by laser Doppler on the dorsal forearm, and HIF-1 alpha expression was determined by immunohistochemical staining in forearm skin biopsies. Results: Skin blood flux during Hypoxia(Skin) and Anoxia(Skin) remained similar to the corresponding Control trial (P = 0.67 and P = 0.81). Immunohistochemically stained epidermal HIF-1 alpha was detected on 8.2 +/- 6.1 and 5.3 +/- 5.7% of the analysed area during Hypoxia(Skin) and Control(1) (P = 0.30) and on 2.3 +/- 1.8 and 2.4 +/- 1.8% during Anoxia(Skin) and Control(2) (P = 0.90) respectively. Conclusion: Reductions in skin-surface PO2 do not affect skin perfusion in humans. The unchanged epidermal HIF-1 alpha expression suggests that epidermal O-2 homoeostasis was not disturbed by Hypoxia(Skin)/Anoxia(Skin), potentially due to compensatory increases in arterial O-2 extraction.
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