Two-year follow-up after a six-week high-intensity training intervention study with breast cancer patients: physiological, psychological and immunological differences.

PURPOSE: Previously we demonstrated the feasibility of a six-week-long combination of high-intensity interval endurance and strength training (HIT/HIRT) for women with nonmetastatic breast cancer leading to improvements in psychological well-being and performance. Now we report results of a 24-month follow-up. METHODS: Previous intervention (IG, n = 10; 58.7 ± 8.4yrs) and control group (CG, n = 9; 58.8 ± 6.6yrs) were asked for follow-up examinations 12 (T12) and 24 months (T24) after cessation of the supervised training (POST). Medical history, mental well-being, performance and immunological variables were analyzed with respect to intervention start (PRE). RESULTS: IG maximum oxygen consumption (⩒O2peak) 12%-improved POST (p = 0.05) and declined to baseline values T24, while CG ⩒O2peak increased 12% T24 (p = 0.01). IG strength (1RM) increased 31% POST (p < 0.001) and remained above baseline level T24 (p = 0.003), whereas CG 1RM slightly improved T24 (+19%, p = 0.034). IG Anxiety and Depression decreased POST and did not change until T24. IG C-reactive protein decreased POST and increased to pre-exercise levels T24. CG immunological/inflammatory/life quality markers did not change. CONCLUSIONS: Six weeks of HIT/HIRT by breast cancer patients can induce similar beneficial effects like two years of convalescence, but outcomes were unstable and showed a fast backslide in aerobic capacity, activity level and in pro-inflammatory state within 12 months.IMPLICATIONS FOR REHABILITATIONHigh-intensity interval endurance and strength training (HIT/HIRT) for female breast cancer patients was shown to improve psychological well-being and performance, but long-term effects/adherence are unknown.Significant backslides in aerobic capacity, activity level as well as in the pro-inflammatory response after one and two years are observed and should be monitored.Continuous supervision and/or support of breast cancer patients before, during, and after medical care due to poor training adherence when voluntarily executed is recommended.

Do skeletal muscle composition and gene expression as well as acute exercise-induced serum adaptations in older adults depend on fitness status?

BACKGROUND: Inactive physical behavior among the elderly is one risk factor for cardiovascular disease, immobility and increased all-cause mortality. We aimed to answer the question whether or not circulating and skeletal muscle biomarkers are differentially expressed depending on fitness status in a group of elderly individuals. METHODS: Twenty-eight elderly individuals (73.36 ± 5.46 years) participated in this exploratory study after participating as part of the multinational SITLESS-clinical trial (implementation of self-management and exercise programs over 16 weeks). A cardiopulmonary exercise test (CPX) and resting skeletal muscle biopsy were performed to determine individual physiological performance capacity. Participants were categorized into a high physical fitness group (HPF) and a low physical fitness group (LPF) depending on peak oxygen uptake (VO2peak). Serum blood samples were taken before (pre) and after (post) CPX and were examined regarding serum BDNF, HSP70, Kynurenine, Irisin and Il-6 concentrations. Skeletal muscle tissue was analyzed by silver staining to determine the myosin heavy chain (MyHC) composition and selected genes by qRT-PCR. RESULTS: HPF showed lower body weight and body fat, while skeletal muscle mass and oxygen uptake at the first ventilatory threshold (VO2T1) did not differ between groups. There were positive associations between VO2peak and VO2VT1 in HPF and LPF. MyHC isoform quantification revealed no differences between groups. qRT-PCR showed higher expression of BDNF and BRCA1 in LPF skeletal muscle while there were no differences in other examined genes regarding energy metabolism. Basal serum concentrations of Irisin were higher in HPF compared to LPF with a trend towards higher values in BDNF and HSP70 in HPF. Increases in Il-6 in both groups were observed post. CONCLUSIONS: Although no association between muscle composition/VO2peak with fitness status in older people was detected, higher basal Irisin serum levels in HPF revealed slightly beneficial molecular serum and muscle adaptations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02629666 . Registered 19 November 2015.

Beneficial Molecular Adaptations In BRCA-Mutation Carriers By Combined HIT/HIRT Intervention: Results From A Pilot Study.

: Based on growing evidence that breast cancer (BRCA) also plays a pivotal role in the regulation of skeletal muscle metabolism and the response to anti-oxidative stress, we examined the influence of regular exercise in human BRCA mutation carriers on their BRCA1 gene/protein expression and inflammatory/oxidative response. Sixteen BRCA-mutation carriers were assigned to an intervention (IG) or control group (CG). IG received a combination of high-intensity interval endurance (HIT) and strength training (HIRT) for six weeks, whereas CG received a low-intensity activity program. Before (T0) and at the end of the intervention (T1), muscle biopsy, physiological performance, blood withdrawal and anthropometry were obtained. Parameters included: Muscle BRCA1 gene/protein expression, inflammatory/oxidative stress, anti-oxidative capacity, peak oxygen capacity (VO2peak) and 1-repetition maximum (1-RM) at six different training machines. VO2peak and 1-RM of IG were increased at T1 compared to T0, whereas CG performance, physiological and molecular parameters remained unchanged. IG showed increased BRCA1 protein concentration as well as anti-oxidative capacity, whereas gene expression was unaltered. IG inflammatory and oxidative damage did not differ between time points. Combined HIT/HIRT increases aerobic and strength performance of BRCA-mutation carriers with up regulated BRCA1 protein expression and improved anti-oxidative status without showing an increased inflammatory response.

Autonomic function may not modulate irisin release in healthy adults: findings from a randomized cross-over study

ABSTRACT Objective Autonomic nervous system, especially the sympathetic nervous system, may stimulate the expression of peroxisome proliferator-activated receptor γ coactivator-1α, which regulates irisin. This study aimed to explore whether there was any association between autonomic function as assessed by heart rate related indices and irisin release following acute exercise. Subjects and methods Seventeen healthy adults were asked to perform an incremental exhaustive cycling as well as an incremental exhaustive running separately on different days. Heart rate was monitored, and blood samples were collected before, immediately, 10-, and 60-minutes post-exercise. Serum irisin was measured using ELISA kit. Results Markers for autonomic function, such as heart rate at rest, peak, or recovery, heart rate reserve, heart rate recovery, and chronotropic index, were comparable between cycling and running (all P > 0.10). Irisin was increased immediately following both exercise. No significant association was observed between heart rate at rest, peak, or recovery and irisin level at the corresponding time-point, as well as between heart rate reserve, heart rate recovery, or chronotropic index and exercise induced irisin release, with or without controlling for age, body mass index, and glucose (all P > 0.10). Conclusions Autonomic function might not be associated with irisin release in healthy adults. Arch Endocrinol Metab. 2020;64(3):201-4

Objectively-Measured Light-Intensity Physical Activity and Risk of Cancer Mortality: A Meta-analysis of Prospective Cohort Studies.

BACKGROUND: The impact of light-intensity physical activity (LPA) in preventing cancer mortality has been questioned. To address this concern, the present meta-analysis aimed to quantify the association between objectively-measured LPA and risk of cancer mortality. METHODS: We conducted a systematic literature search in PubMed and Scopus to January 2020. Prospective cohort studies reporting the association between objectively-measured LPA using activity monitors (e.g., accelerometers) and risk of cancer mortality in the general population were included. The summary hazard ratios (HR) per 30 min/day of LPA and 95% confidence intervals (CI) were obtained using a random-effects model. Dose-response analysis was used to plot their relationship. RESULTS: Five prospective cohort studies were included, in which the definition of LPA based on accelerometer readings was mainly set within 100 to 2,100 counts/min. The summary HR for cancer mortality per 30 min/day of LPA was 0.86 (95% CI, 0.79-0.95; I 2 < 1%), and the association between LPA and risk reduction in cancer mortality was linearly shaped (P nonlinearity = 0.72). LPA exhibited a comparable magnitude of risk reduction in cancer mortality of moderate-to-vigorous physical activity regardless of equal time-length (0.87 per 30 min/day vs. 0.94 per 30 min/day, P interaction = 0.46) or equal amount (0.74 vs. 0.94 per 150 metabolic equivalents-min/day, P interaction = 0.11). Furthermore, replacing sedentary time by LPA of 30 min/day decreased the risk of cancer mortality by 9%. CONCLUSIONS: Objectively-measured LPA conferred benefits in decreasing the risk of cancer mortality. IMPACT: LPA should be considered in physical activity guidelines to decrease the risk of cancer mortality.

Increased Hepcidin Levels During a Period of High Training Load Do Not Alter Iron Status in Male Elite Junior Rowers.

The liver-derived hormone hepcidin plays a key role in iron metabolism by mediating the degradation of the iron export protein ferroportin 1 (FPN1). Circulating levels of hepcidin and the iron storage protein ferritin are elevated during the recovery period after acute endurance exercise, which can be interpreted as an acute phase reaction to intense exercise with far-reaching consequences for iron metabolism and homeostasis. Since absolute and functional iron deficiency (ID) potentially lead to a loss of performance and well-being, it is surprising that the cumulative effects of training stress on hepcidin levels and its interplay with cellular iron availability are not well described. Therefore, the aim of this study was to determine serum levels of hepcidin at six time points during a 4-week training camp of junior world elite rowers preparing for the world championships and to relate the alterations in training load to overall iron status determined by serum ferritin, transferrin, iron, and soluble transferrin receptor (sTfR). Serum hepcidin levels increased significantly (p = 0.02) during the initial increase in training load (23.24 ± 2.43 ng/ml) at day 7 compared to the start of training camp (11.47 ± 3.92 ng/ml) and turned back on day 13 (09.51 ± 3.59 ng/ml) already, meeting well the entrance level of hepcidin at day 0. Serum ferritin was significantly higher at day 7 compared to all other timepoints with exception of the subsequent time point at day 13 reflecting well the time course pattern of hepcidin. Non-significant changes between training phases were found for serum iron, transferrin, and sTfR levels as well as for transferrin saturation, and ferritin-index (sTfR/log ferritin). Our findings indicate that hepcidin as well as ferritin, both representing acute phase proteins, are sensitive to initial increases in training load. Erythropoiesis was unaffected by iron compartmentalization through hepcidin. We conclude that hepcidin is sensitive to rigorous changes in training load in junior world elite rowers without causing short-term alterations in functional iron homeostasis.

Circulating irisin in patients with polycystic ovary syndrome: a meta-analysis.

There is growing interest in exploring circulating (plasma/serum) irisin in polycystic ovary syndrome (PCOS) patients. This meta-analysis aimed to summarize the evidence assessing circulating irisin changes in this population. A systematic search was conducted in three databases: PubMed, Cochrane Library and Web of Science, for studies reporting irisin in PCOS patients compared with healthy controls or stratified by body mass index (BMI), or assessing irisin response to hyperinsulinemia. Effect sizes (Cohen's d with 95% confidence intervals [CI]) were calculated using random-effects models. Eight studies with 918 PCOS patients and 528 healthy controls were included. Results showed that circulating irisin was higher in PCOS patients than in overall healthy controls (d = 0.37, 95% CI 0.05 to 0.70), but not compared with BMI-matched or age- and BMI-matched controls. Circulating irisin was higher in PCOS patients with higher BMI than lower (d = 0.36, 95% CI 0.16 to 0.56). Circulating irisin decreased 2 h later in response to euglycemic hyperinsulinemia in PCOS patients with a larger magnitude than healthy controls (d = -0.32, 95% CI -0.53 to -0.11). In summary, with adjustment for BMI, circulating irisin in PCOS patients seems comparable to healthy controls, but its response to hyperinsulinemia might be impaired.

Feasibility and effects of a combined adjuvant high-intensity interval/strength training in breast cancer patients: a single-center pilot study.

PURPOSE: To evaluate feasibility of an exercise intervention consisting of high-intensity interval endurance and strength training in breast cancer patients. METHODS: Twenty-six women with nonmetastatic breast cancer were consecutively assigned to the exercise intervention- (n= 15, mean age 51.9 ± 9.8 years) and the control group (n = 11, mean age 56.9 ± 7.0 years). Cardiopulmonary exercise testing that included lactate sampling, one-repetition maximum tests and a HADS-D questionnaire were used to monitor patients both before and after a supervised six weeks period of either combined high-intensity interval endurance and strength training (intervention group, twice a week) or leisure training (control group). RESULTS: Contrarily to the control group, endurance (mean change of VO2, peak 12.0 ± 13.0%) and strength performance (mean change of cumulative load 25.9 ± 11.2%) and quality of life increased in the intervention group. No training-related adverse events were observed. CONCLUSIONS: Our guided exercise intervention could be used effectively for initiation and improvement of performance capacity and quality of life in breast cancer patients in a relatively short time. This might be especially attractive during medical treatment. Long-term effects have to be evaluated in randomized controlled studies also with a longer follow-up. Implications for Rehabilitation High-intensity interval training allows improvement of aerobic capacity within a comparable short time. Standard leisure training in breast cancer patients is rather suitable for the maintenance of performance capacity and quality of life. Guided high-intensity interval training combined with strength training can be used effectively for the improvement of endurance and strength capacity and also quality of life. After exclusion of contraindications, guided adjuvant high-intensity interval training combined with strength training can be safely used in breast cancer patients.

Ribosomal transcription is regulated by PGC-1alpha and disturbed in Huntington's disease.

PGC-1α is a versatile inducer of mitochondrial biogenesis and responsive to the changing energy demands of the cell. As mitochondrial ATP production requires proteins that derive from translation products of cytosolic ribosomes, we asked whether PGC-1α directly takes part in ribosomal biogenesis. Here, we show that a fraction of cellular PGC-1α localizes to the nucleolus, the site of ribosomal transcription by RNA polymerase I. Upon activation PGC-1α associates with the ribosomal DNA and boosts recruitment of RNA polymerase I and UBF to the rDNA promoter. This induces RNA polymerase I transcription under different stress conditions in cell culture and mouse models as well as in healthy humans and is impaired already in early stages of human Huntington's disease. This novel molecular link between ribosomal and mitochondrial biogenesis helps to explain sarcopenia and cachexia in diseases of neurodegenerative origin.

High-resolution respirometry of fine-needle muscle biopsies in pre-manifest Huntington's disease expansion mutation carriers shows normal mitochondrial respiratory function.

Alterations in mitochondrial respiration are an important hallmark of Huntington's disease (HD), one of the most common monogenetic causes of neurodegeneration. The ubiquitous expression of the disease causing mutant huntingtin gene raises the prospect that mitochondrial respiratory deficits can be detected in skeletal muscle. While this tissue is readily accessible in humans, transgenic animal models offer the opportunity to cross-validate findings and allow for comparisons across organs, including the brain. The integrated respiratory chain function of the human vastus lateralis muscle was measured by high-resolution respirometry (HRR) in freshly taken fine-needle biopsies from seven pre-manifest HD expansion mutation carriers and nine controls. The respiratory parameters were unaffected. For comparison skeletal muscle isolated from HD knock-in mice (HdhQ111) as well as a broader spectrum of tissues including cortex, liver and heart muscle were examined by HRR. Significant changes of mitochondrial respiration in the HdhQ knock-in mouse model were restricted to the liver and the cortex. Mitochondrial mass as quantified by mitochondrial DNA copy number and citrate synthase activity was stable in murine HD-model tissue compared to control. mRNA levels of key enzymes were determined to characterize mitochondrial metabolic pathways in HdhQ mice. We demonstrated the feasibility to perform high-resolution respirometry measurements from small human HD muscle biopsies. Furthermore, we conclude that alterations in respiratory parameters of pre-manifest human muscle biopsies are rather limited and mirrored by a similar absence of marked alterations in HdhQ skeletal muscle. In contrast, the HdhQ111 murine cortex and liver did show respiratory alterations highlighting the tissue specific nature of mutant huntingtin effects on respiration.

Exercise is a potent stimulus for enhancing circulating DNase activity.

OBJECTIVES: To elucidate cell free DNA (cfDNA) clearance kinetics following an acute bout of high intensity exercise by measuring circulating DNase activity reduction (AR). DESIGN AND METHODS: Serum cfDNA concentration and DNase-AR were measured prior to and post (immediately post, 7 and 30 min post) an acute bout of rowing exercise until exhaustion. RESULTS: Serum cfDNA concentration was significantly (P ≤ .001) elevated immediately post (2.5-fold) and 7 min post exercise (2.3-fold) with a return close to baseline at 30 min post exercise (1.5-fold). The rise in cfDNA was accompanied by a concomitant, significant (P ≤ .001) decrease in serum DNase-AR from 15.1% prior to exercise to 3.1% AR at cessation of the exercise test and 7 min post exercise (3.9% AR). DNase-AR returned close to baseline at 30 min post exercise (5.2% AR). CONCLUSIONS: A single bout of high intensity exercise is a potent stimulus for enhancing circulating DNase activity in healthy people. Acute exercise may therefore be considered as a non-pharmacological stimulus to trigger DNase activity. This finding may be relevant for pathological conditions associated with increased cfDNA concentrations like cystic fibrosis, where pharmacological recombinant human DNase (rhDNase) treatment has been successfully used to improve patients' health and physical function.

Heat shock protein 70 (Hsp70) inhibits oxidative phosphorylation and compensates ATP balance through enhanced glycolytic activity.

To address possible effects of heat shock protein 70 (Hsp70) on energy metabolism, we established a cell line expressing different levels of Hsp70 and evaluated changes in glucose and lactate metabolites, as well as ATP levels accordingly. In addition, activities of enzymes involved in glycolysis [phosphofructokinase (PFK) and lactate dehydrogenase (LDH)], Krebs cycle [citric synthase (CS)], and oxidative phosphorylation {NADH dehydrogenase [complex I (CI)] and ubiquinol:cytochrome-c reductase [complex III (CIII)]} were analyzed. The results show that both glucose consumption and lactate excretion were elevated significantly in cells expressing increased levels of Hsp70. Simultaneously, the activities of glycolytic enzymes PFK and LDH were increased markedly in cells overexpressing Hsp70. Activities of enzymes CI and CIII, both involved in oxidative phosphorylation, decreased upon increased expression of Hsp70. These findings were supported by nonsignificant reductions of CS activities in cells that overexpressed Hsp70, whereas intracellular ATP levels remained constant over a wide range of Hsp70 expression. In conclusion, overexpression of Hsp70 in HeLa cells results in downregulation of oxidative phosphorylation, in particular, multiprotein CIII, the main source of reactive oxygen species. In exchange, upregulation of the glycolytic pathway compensates for the homeostasis of cellular ATP supply.

CD34+CD140b+ cells and circulating CXCL12 correlate with the angiographically assessed severity of cardiac allograft vasculopathy.

AIMS: We sought to determine whether circulating vascular progenitor cells, such as endothelial progenitor cells (EPCs) or smooth muscle progenitor cells (SPCs), were associated with the severity of cardiac allograft vasculopathy (CAV). METHODS AND RESULTS: CD34(+)CD140b(+) SPCs and CD34(+)KDR(+) EPCs were measured in the peripheral circulation of 187 adult heart transplant recipients by flow cytometry. Cardiac allograft vasculopathy was quantified by angiography using a CAV-specific scoring system. Cardiac allograft vasculopathy was present in 84 patients (44.7%) and was classified as mild in 59 and severe in 25 cases. Circulating SPCs were more frequently detectable in CAV patients than in patients without CAV. The number of CD34(+)CD140b(+) cells showed a stepwise increase in patients with moderate and severe CAV. Smooth muscle progenitor cell counts were higher in patients with coronary stent implant compared with unstented patients with CAV. In contrast, peripheral CD34(+)KDR(+) EPC counts were not changed in CAV patients. Plasma CXCL12 levels correlated with the degree of CAV and SPC counts. None of the different immunosuppressive drug regimes was related to the SPC count or the CXCL12 levels. A multivariate regression analysis revealed that the SPC count was independently associated with the presence of CAV. CONCLUSION: Circulating SPCs, but not EPCs, and plasma CXCL12 concentrations are elevated in CAV patients, indicating that they play prominent roles in transplant arteriosclerosis.

Lysophosphatidic acid receptors LPA1 and LPA3 promote CXCL12-mediated smooth muscle progenitor cell recruitment in neointima formation.

RATIONALE: The chemokine CXCL12 (CXC motif ligand 12) and its receptor CXCR 4 (CXC motif receptor 4) direct the recruitment of smooth muscle progenitor cells (SPCs) in neointima formation after vascular injury. Lysophosphatidic acid (LPA) induces CXCL12 and neointimal accumulation of smooth muscle cells (SMCs) in uninjured arteries. Thus, we hypothesize that LPA may regulate CXCL12-mediated vascular remodelling. OBJECTIVES: We evaluated the role of LPA receptors in initiating CXCL12-dependent vascular repair by SPCs. METHODS AND RESULTS: Wire-induced carotid injury was performed in apolipoprotein E(-/-) mice on western-type diet. LPA receptor expression was studied by immunostaining and quantitative RT-PCR. LPA receptors LPA(1) and LPA(3) were detected in the media of uninjured arteries and in the injury-induced neointima. LPA(3) mRNA was upregulated and LPA(1) mRNA downregulated at one week after injury. The LPA(1/3) antagonist Ki16425 inhibited neointima formation by 71% and reduced both relative neointimal SMCs and the macrophage content. Additionally, neointimal hypoxia-inducible factor-1alpha and CXCL12 expression, the injury-induced peripheral stem cell antigen-1 (Sca-1)(+)/Lin(-) SPC mobilization, and the neointimal recruitment of Sca-1(+)SMCs were inhibited by Ki16425. In wild type mice, LPA20:4 increased CXCL12 and hypoxia-inducible factor-1alpha expression in carotid arteries as early as 1 day following short-term endoluminal incubation. LPA20:4-induced SPC mobilization and neointima formation were blocked by Ki16425, LPA(1)- and LPA(3)-specific small interfering (si)RNA, and the CXCR4 antagonist POL5551. Ki16425 reduced LPA20:4-mediated neointimal recruitment of SPC as demonstrated by 2-photon microscopy in bone marrow chimeric mice after repopulation with SM22-LacZ transgenic, hematopoietic cells. Moreover, POL5551 decreased the neointimal accumulation of CXCR4(+) SMCs. CONCLUSIONS: LPA(1) and LPA(3) promote neointima formation through activation of CXCL12-mediated mobilization and recruitment of SPCs.