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The incidence of breast cancer has increased from 900 000 to 2.3 million new annual cases over the last 25 years. The 5-year survival rate has markedly risen to over 90% worldwide due to significant therapeutic advancements. Longer survival in patients with breast cancer means more patients may experience long-term effects of their treatments, including cancer therapy-related cardiac dysfunction (CTRCD). To date, there is no established primary prevention to minimise CTRCD. The Cardiac Health in Breast Cancer study is a two-arm, single-centre, randomised controlled trial investigating the impact of an exercise programme on cardiac changes in patients with breast cancer undergoing cardiotoxic cancer therapy. 48 females with breast cancer will be randomised to either a 12-month intervention group (IG) or a control group (CG). The IG will receive a combination of supervised high-intensity interval training (HIIT) and high-intensity resistance training (HIRT) for 6 months, while the CG will follow WHO guidelines for physical activity independently. All participants will undergo transthoracic echocardiography, cardiac magnetic resonance (CMR) imaging and cardiopulmonary exercise testing at baseline, after 6 months and after 12 months. The primary endpoint is the occurrence of symptomatic or asymptomatic CTRCD at the time points of examination, detected by cardiac imaging, which may be mitigated by structured physical exercise. Secondary endpoints include assessments of cardiac inflammation as detected by CMR, mitochondrial dysfunction, health-related quality of life, the occurrence of fatigue, depression and anxiety, as well as exercise capacity, average heart rate, heart rate variability and daily physical activity., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/objectives: Myocardial involvement has been observed in athletes following SARS-CoV-2 infection. It is unclear if these changes are due to myocardial damage per se or to an interruption in training. The aim of this study was to assess cardiac function and structure in elite athletes before and after infection (INFAt) and compare them to a group of healthy controls (CON)., Methods: Transthoracic echocardiography was performed in 32 elite athletes, including 16 INFAt (median 21.0 (19.3-21.5) years, 10 male) before (t 0 ) and 52 days after (t 1 ) mild SARS-CoV-2 infection and 16 sex-, age- and sports type-matched CON. Left and right ventricular global longitudinal strain (LV/RV GLS), RV free wall longitudinal strain (RV FWS) and left atrial strain (LAS) were assessed by an investigator blinded to patient history., Results: INFAt showed no significant changes in echocardiographic parameters between t 0 and t 1 , including LV GLS (-21.8% vs. -21.7%, p = 0.649) and RV GLS (-29.1% vs. -28.7%, p = 0.626). A significant increase was observed in LA reservoir strain (LASr) (35.7% vs. 47.8%, p = 0.012). Compared to CON, INFAt at t 1 had significantly higher RV FWS (-33.0% vs. -28.2%, p = 0.011), LASr (47.8% vs. 30.5%, p < 0.001) and LA contraction strain (-12.8% vs. -4.9%, p = 0.050) values., Conclusions: In elite athletes, mild SARS-CoV-2 infection does not significantly impact LV function when compared to their pre-SARS-CoV-2 status and to healthy controls. However, subtle changes in RV and LA strain may indicate temporary or training-related adaptions. Further research is needed, particularly focusing on athletes with more severe infections or prolonged symptoms.

Inhaled beta-2 adrenoceptor agonists (iβ2A) are routinely used as bronchodilators in the treatment of asthma. However, their cardiac effects in athletes are scarcely examined. Thus, the aim of this study was to evaluate the effects of iβ2A on left ventricular (LV) systolic function (SF) by echocardiography in healthy, non-asthmatic female and male endurance athletes. A randomized, double-blinded, placebo-controlled, balanced, 4-way complete block cross-over study was conducted. Twenty-four healthy athletes (12f/12m: 22.9 ± 2.7/24.4 ± 4.6 years) randomly completed 4 study arms (placebo; salbutamol; formoterol; formoterol + salbutamol). After inhalation of the study medication, the participants performed a 10-min time trial (TT) on a bicycle ergometer. After each TT an echocardiography was performed to determine LVSF. Blood samples were collected pre, post, 3 h and 24 h post TT. In females, total serum concentrations for salbutamol and formoterol were higher. LV ejection fraction (LVEF) and LV global longitudinal strain (LVendoGLS) showed a treatment effect for the whole study group (p < 0.0001) and a sex effect on LVEF (p = 0.0085). In women, there was a significant treatment effect for all medication arms (at least p ≤ 0.01) both on LVEF and LVendoGLS. In men only formoterol and formoterol + salbutamol displayed a treatment effect on LVEF (p = 0.0427, p = 0.0330; respectively), whereas on LVendoGLS only formoterol + salbutamol was significant (p = 0.0473). The iβ2A significantly influenced LVSF after an acute bout of exercise in healthy endurance athletes. These effects were even more pronounced when combining both iβ2A that supports a dose-dependent effect on cardiac function. Moreover, female athletes had higher serum concentrations of β2 agonists and stronger effects on LVSF compared to male athletes. This is mainly explained by differences in body weight and related plasma volume and may indicate a potential risk when increasing dose above the tested concentrations. Trial registration: At the European Union Drug Regulating Authorities Clinical Trials (Eudra CT) with the number 201,500,559,819 (registered prospectively on 09/12/2015) and at the German register for clinical studies (DRKS number 00010574 registered retrospectively on 16/11/2021)., (© 2024. The Author(s).)

Background: Exercise and the consumption of sugars result in a dysfunction of the intestinal barrier (IB). Here, we determined the effect of sugar in a natural matrix on the intestinal barrier after moderate (A) and intensive endurance exercise (B)., Method: The IB function was determined before (pre) and after running (post), and 120 and 180 min after consuming the drink by measuring serum endotoxin concentrations (lipopolysaccharides-LPS), IL-6, CD14, and i-FABP. In study A, nonspecifically trained participants ( n = 24, males and females, age 26 ± 4) ran for one hour at 80% of their individual anaerobic threshold (IAT). After finishing, the runners consumed, in a crossover setup, either 500 mL of water, diluted cloudy apple juice (test drink), or an identical drink (placebo) without the fruit juice matrix (FJM). In study B, the participants ( n = 30, males and females, age 50 ± 9) completed an ultra-marathon run, were divided into groups, and consumed one of the above-mentioned drinks., Results: Study A: Exercise resulted in a significant increase in serum LPS, i-FABP, and IL-6, which decreased fast after finishing. No impact of the different drinks on LPS i-FABP, or IL-6 could be observed, but there was an impact on CD14. Study B: The ultra-marathon resulted in a strong increase in serum LPS, which decreased fast after finishing in the water and test drink groups, but not in the placebo group., Conclusions: The consumed drinks did not affect the kinetics of IB regeneration after moderate exercise, but impacted CD14 serum concentrations, indicating possible beneficial effects of the FJM on the immune system. After an ultra-marathon, IB function regenerates very fast. The intake of sugar (placebo) seems to have had a negative impact on IB regeneration, which was diminished by the presence of the FJM.

Background: An infection with SARS-CoV-2 can lead to a variety of symptoms and complications, which can impair athletic activity., Objective: We aimed to assess the clinical symptom patterns, diagnostic findings, and the extent of impairment in sport practice in a large cohort of athletes infected with SARS-CoV-2, both initially after infection and at follow-up. Additionally, we investigated whether baseline factors that may contribute to reduced exercise tolerance at follow-up can be identified., Methods: In this prospective, observational, multicenter study, we recruited German COVID elite-athletes (cEAs, n = 444) and COVID non-elite athletes (cNEAs, n = 481) who tested positive for SARS-CoV-2 by PCR (polymerase chain reaction test). Athletes from the federal squad with no evidence of SARS-CoV-2 infection served as healthy controls (EAcon, n = 501). Questionnaires were used to assess load and duration of infectious symptoms, other complaints, exercise tolerance, and duration of training interruption at baseline and at follow-up 6 months after baseline. Diagnostic tests conducted at baseline included resting and exercise electrocardiogram (ECG), echocardiography, spirometry, and blood analyses., Results: Most acute and infection-related symptoms and other complaints were more prevalent in cNEA than in cEAs. Compared to cEAs, EAcon had a low symptom load. In cNEAs, female athletes had a higher prevalence of complaints such as palpitations, dizziness, chest pain, myalgia, sleeping disturbances, mood swings, and concentration problems compared to male athletes (p < 0.05). Until follow-up, leading symptoms were drop in performance, concentration problems, and dyspnea on exertion. Female athletes had significantly higher prevalence for symptoms until follow-up compared to male. Pathological findings in ECG, echocardiography, and spirometry, attributed to SARS-CoV-2 infection, were rare in infected athletes. Most athletes reported a training interruption between 2 and 4 weeks (cNEAs: 52.9%, cEAs: 52.4%), while more cNEAs (27.1%) compared to cEAs (5.1%) had a training interruption lasting more than 4 weeks (p < 0.001). At follow-up, 13.8% of cNEAs and 9.9% of cEAs (p = 0.24) reported their current exercise tolerance to be under 70% compared to pre-infection state. A persistent loss of exercise tolerance at follow-up was associated with persistent complaints at baseline, female sex, a longer break in training, and age > 38 years. Periodical dichotomization of the data set showed a higher prevalence of infectious symptoms such as cough, sore throat, and coryza in the second phase of the pandemic, while a number of neuropsychiatric symptoms as well as dyspnea on exertion were less frequent in this period., Conclusions: Compared to recreational athletes, elite athletes seem to be at lower risk of being or remaining symptomatic after SARS-CoV-2 infection. It remains to be determined whether persistent complaints after SARS-CoV-2 infection without evidence of accompanying organ damage may have a negative impact on further health and career in athletes. Identifying risk factors for an extended recovery period such as female sex and ongoing neuropsychological symptoms could help to identify athletes, who may require a more cautious approach to rebuilding their training regimen., Trial Registration Number: DRKS00023717; 06.15.2021-retrospectively registered., (© 2024. The Author(s).)

Patients suffering from chronic fatigue syndrome (CFS) or post-COVID syndrome (PCS) exhibit a reduced physiological performance capability. Impaired mitochondrial function and morphology may play a pivotal role. Thus, we aimed to measure the muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity and assess mitochondrial morphology in CFS and PCS patients in comparison to healthy controls (HCs). Mitochondrial OXPHOS capacity was measured in permeabilized muscle fibers using high-resolution respirometry. Mitochondrial morphology (subsarcolemmal/intermyofibrillar mitochondrial form/cristae/diameter/circumference/area) and content (number and proportion/cell) were assessed via electron microscopy. Analyses included differences in OXPHOS between HC, CFS, and PCS, whereas comparisons in morphology/content were made for CFS vs. PCS. OXPHOS capacity of complex I, which was reduced in PCS compared to HC. While the subsarcolemmal area, volume/cell, diameter, and perimeter were higher in PCS vs. CFS, no difference was observed for these variables in intermyofibrillar mitochondria. Both the intermyofibrillar and subsarcolemmal cristae integrity was higher in PCS compared to CFS. Both CFS and PCS exhibit increased fatigue and impaired mitochondrial function, but the progressed pathological morphological changes in CFS suggest structural changes due to prolonged inactivity or unknown molecular causes. Instead, the significantly lower complex I activity in PCS suggests probably direct virus-induced alterations.

Interactions between statin therapy and physical exercise complicate effective cardiovascular prevention. Emerging evidence suggests that muscle strain related changes in the expression of the glucocorticoid-induced leucine zipper (GILZ) may be involved. Therefore, we measured GILZ mRNA expression levels in M. vastus lateralis samples of 32 healthy individuals before and after a standardized bout of strength or endurance exercise. Overall, we found a highly significant downregulation of GILZ after exercise training (p < 0.001). Within-subgroup changes were statistically significant only after strength training, supporting the role of muscle (as opposed to cardiocirculatory) strain. If confirmed, this may help fitting training recommendations and medication., Competing Interests: Declaration of interest statement The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: It has not yet been conclusively determined whether reduced left ventricular global longitudinal strain (LV GLS) after COVID-19 contributes to a reduction in exercise capacity. Our own studies showed a possible mild myocardial involvement in the form of reduced LV GLS in athletes after COVID-19 compared with healthy athletes. The aims of this prospective follow-up study were to investigate the development of LV GLS over a 3-month period in athletes after COVID-19 and the possible relationship between LV GLS and physical performance., Methods: LV GLS was determined in four-, two-, and three-chamber views and assessed offline by a blinded investigator in 96 recreational athletes (mean age 33.15 ± 12.40 years, 53 male, peak VO 2 38.82 ± 11.14 ml/min/kg) at a median of two ( t 0 ) and five months ( t 1 ) after COVID-19. Cardiopulmonary exercise testing (CPET) was performed on a bicycle ergometer on both examination dates., Results: LV GLS improved significantly between t 0 and t 1 ( t 0 -18.82 ± 2.02 vs. t 1 -19.46 ± 2.05, p  < 0.001). Echocardiographic and spiroergometric parameters were within the normal clinical reference range. Maximum power increased significantly from t 0 to t 1 ( t 0 283.17 ± 83.20 vs. t 1 286.24 ± 85.22 Watt, p  = 0.009) and there was a trend toward increased peak oxygen uptake ( t 0 36.82 ± 11.14 vs. t 1 38.68 ± 10.26 ml/min/kg, p  = 0.069). We found no correlation between LV GLS and performance parameters, except for the respiratory exchange ratio (RER) [ ρ -0.316, (-0.501; -0.102), p  < 0.050]., Conclusions: Significant improvement in LV GLS approximately five months after COVID-19 may be due to mild myocardial involvement during or shortly after COVID-19, which seems to recover. There was no correlation between LV GLS and performance parameters, except for an inverse correlation of LV GLS and RER, suggesting insufficient exercise intolerance at lower GLS values. Further studies on the development of GLS in athletes or in the general population with moderate and severe disease courses would be informative as well as the comparison of pre-COVID-19 with post-COVID-19 echocardiography to evaluate the effects of COVID-19 on cardiac function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Schellenberg, Matits, Bizjak, Kersten, Kirsten, Vollrath and Steinacker.)

Background: High prevalence rates of β2-agonist use among athletes in competitive sports makes it tempting to speculate that illegitimate use of β2-agonists boosts performance. However, data regarding the potential performance-enhancing effects of inhaled β2-agonists and its underlying molecular basis are scarce., Methods: In total, 24 competitive endurance athletes (12f/12m) participated in a clinical double-blinded balanced four-way block cross-over trial to investigate single versus combined effects of β2-agonists salbutamol (SAL) and formoterol (FOR), to evaluate the potential performance enhancement of SAL (1200 µg, Cyclocaps, Pb Pharma GmbH), FOR (36 µg, Sandoz, HEXAL AG) and SAL + FOR (1200 µg + 36 µg) compared to placebo (PLA, Gelatine capsules containing lactose monohydrate, Pharmacy of the University Hospital Ulm). Measurements included skeletal muscle gene and protein expression, endocrine regulation, urinary/serum β2-agonist concentrations, cardiac markers, cardiopulmonary and lung function testing and the 10-min time trial (TT) performance on a bicycle ergometer as outcome variables. Blood and urine samples were collected pre-, post-, 3 h post- and 24 h post-TT., Results: Mean power output during TT was not different between study arms. Treatment effects regarding lung function (p < 0.001), echocardiographic (left ventricular end-systolic volume p = 0.037; endocardial global longitudinal strain p < 0.001) and metabolic variables (e.g. NR4A2 and ATF3 pathway) were observed without any influence on performance. In female athletes, total serum β2-agonist concentrations for SAL and FOR were higher. Microarray muscle gene analysis showed a treatment effect for target genes in energy metabolism with strongest effect by SAL + FOR (NR4A2; p = 0.001). Of endocrine variables, follicle-stimulating hormone (3 h Post-Post-TT), luteinizing hormone (3 h Post-Pre-TT) and insulin (Post-Pre-TT) concentrations showed a treatment effect (all p < 0.05)., Conclusions: No endurance performance-enhancing effect for SAL, FOR or SAL + FOR within the permitted dosages compared to PLA was found despite an acute effect on lung and cardiac function as well as endocrine and metabolic variables in healthy participants. The impact of combined β2-agonists on performance and sex-specific thresholds on the molecular and cardiac level and their potential long-term performance enhancing or health effects have still to be determined., Trial Registration: Registered at Eudra CT with the number: 2015-005598-19 (09.12.2015) and DRKS with number DRKS00010574 (16.11.2021, retrospectively registered)., (© 2023. Springer Nature Switzerland AG.)

Introduction: Fatigue is a common symptom in post-COVID-19 patients. Individuals with fatigue often perform less well compared to healthy peers or without fatigue. It is not yet clear to what extent fatigue is related to the inability to reach maximum exhaustion during physical exercise., Methods: A symptom-based questionnaire based on the Carruthers guidelines (2003) was used for reporting the presence of fatigue and further symptoms related to COVID-19 from 85 participants (60.0% male, 33.5 ± 11.9 years). Cardiopulmonary exercise testing (CPET) and lactate measurement at the end of the test were conducted. Objective and subjective exhaustion criteria according to Wasserman of physically active individuals with fatigue (FS) were compared to those without fatigue (NFS)., Results: Differences between FS and NFS were found in Peak V̇O 2 /BM (p < 0.001) and Max Power/BM (p < 0.001). FS were more likely to suffer from further persistent symptoms (p < 0.05). The exhaustion criterion Max. lactate was reached significantly more often by NFS individuals., Conclusion: Although the aerobic performance (Max Power/BM) and the metabolic rate (Peak V̇O 2 /BM and Max. lactate) of FS were lower compared to NFS, they were equally able to reach objective exhaustion criteria. The decreased number of FS who reached the lactate criteria and the decreased V̇O 2 peak indicates a change in metabolism. Other persistent post-COVID-19 symptoms besides fatigue may also impair performance, trainability and the ability to reach objective exhaustion. Trial registration Trial registration: DRKS00023717; date of registration: 15.06.2021 (retrospectively registered)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Blood profiling data in athletic populations and their respective responses to SARS-CoV-2 infection are lacking. Thus, this exploratory pilot study aimed to analyze and compare clinical blood markers in previously infected trained athletes (ATH; 30 m/29 f) and a not previously infected healthy athletic control group (HC; 12 m/19 f). The ATH group undertook a sports medical examination which included extended blood analyses. Blood profiles with a total of 74 variables were assessed (blood counts, pro-/inflammatory and immunological markers, and micronutrients), and the ATH group was compared to the age-matched, vaccinated HC group with comparable athletic back grounds, though without previous SARS-CoV-2-infections. The ATH group showed lower IgG, Troponin-T levels, and they had a lower complement/acute-phase protein activation. Furthermore, Vitamin D levels were lower and electrolyte/micronutrient concentrations were higher in ATH. Soluble transferrin receptor as a marker of erythrocyte turnover was decreased whereas PTT as a coagulation marker was increased. Subgroup analyses according to sex revealed more differences between the women of the ATH and HC groups (for 25 different variables) than between the men (for 5 different variables), especially for immunological and metabolic variables. In particular, the immune system and electrolyte/micronutrient status should be observed frequently and sex-specifically in this athletic cohort.

Background: SARS-CoV-2 infection is a risk factor for the development of depressive symptoms such as lack of energy, loss of interest, and depressed mood. Inflammatory processes might underline this association. The aim of this study was to investigate the association between inflammatory markers and the severity of depression after SARS-CoV-2 infection and the predictive effect of inflammatory markers on the severity of depressive symptoms. Lifestyle factors and lifestyle-related diseases can influence inflammation and depressive symptoms. As these lifestyle factors and lifestyle-related diseases are less common in physically active individuals, they are a suitable population for investigating this research question., Methods: We investigated 61 at least moderate physically active individuals on average ∼6 months ( SD  = 4.22, range = 0.5-19 months) after SARS-CoV-2 infection (t 0 ) and performed a follow-up after 3 months (t 1 ). Depressive symptoms and biomarkers of inflammation (interleukin [IL]-1β, IL-8, IL-10, Ferritin, Lipopolysaccharide-binding-protein [LBP], neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], lymphocyte-to-monocyte ratio [LMR]) and kynurenine [KYN] were measured at both time points. Concentrations of inflammatory markers at t 0 were used to predict the severity of depressive symptoms at t 0 and t 1 ., Results: Concentrations of KYN were negatively related to the severity of depressive symptoms at t 0. Concentrations of LMR predicted higher depressive symptoms at t 0 as well as at t 1 . Furthermore, individuals with lower concentrations of LBP at t 0 showed a higher severity of depressive symptoms at t 1 . No correlation was found between severity of depressive symptoms and IL-1β, IL-8, IL-10, ferritin, NLR, and PLR at both time points., Conclusions: KYN, LBP and LMR might be useful as a predictive factor of depressive symptoms in physically active individuals after SARS-CoV-2 infection. While the results for KYN confirm the current scientific evidence, our results highlight the importance of the innovative inflammatory markers LMR and LBP. LMR and LBP might be interesting targets for predicting the development of depressive symptoms in SARS-CoV-2 infected populations and should be further investigated in future studies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Low aerobic capacity is associated with an increased mortality risk in allogenic stem-cell transplantation (alloSCT) patients, but currently used risk scores in the pre-transplantation workup are still underestimating physical activity as a prognostic factor., Aim: To examine the physical condition, muscle function, blood inflammation and training adherence of alloSCT patients during inpatient time to identify potential biomarkers associated with development of myopathy and sarcopenia., Methods: Patients undergoing alloSCT were examined at four time points (T0: before alloSCT; T ha : hospital admission; T1: engraftment; T2: inpatient discharge). T0 included cardiopulmonary performance, body composition, grip and knee strength, motor skill tests (One-leg stand/Tinetti/Chair-rising), blood sampling (blood cell profiling and inflammation targets (Kynurenin/high sensitivity C-reactive Protein (hsCRP)/Tumor necrosis factor alpha (TNF-alpha)/Musclin/Galectin-3) and quality of life, state of health, fatigue, muscle weakness and physical activity by questionnaires (IPAQ/BSA/SARC-F/Fatigue). At T1 and T2, blood samples, grip strength and motor skill tests were repeated. Glucocorticoid dose and daily physical activity were documented during inpatient stay., Results: 26 of 35 included patients (4 females; age 55.58 ± 12.32 years; BMI 24.70 ± 3.27 kg/m 2 ; VO 2peak 16.55 ± 4.06 ml/min/kg) could proceed to alloSCT. Grip strength and Tinetti decreased from T0 until T2, no difference in Chair-rising test, One-leg and Tandem stand. All patients engrafted after 24.9 days ± 3.9 days. HsCRP and Kynurenine increased from T0 to T1, decreased at T2. TNF-alpha (T0vsT2/T1vsT2) and Musclin (T0vsT1) decreased. At T2, Galectin-3 was higher compared to T0/T1. Correlation analysis of grip strength and inflammatory markers revealed a positive correlation with TNF-alpha at T2. 50% of patients documented physical activity and questionnaire and reported a 50%-reduction of daily endurance and strength training between T1 to T2., Conclusion: Allogeneic stem-cell transplantation is associated with immune system vulnerability due to conditioning, increased inflammation and fatigue, and loss of muscle strength and function. In addition to hsCRP, Kynurenine seems to be a reliable biomarker to monitor acute and regenerative inflammation status of alloSCT patients, while Musclin and Galectin-3 may be added to physiological assessment regarding myopathy and sarcopenia. Grip strength and daily activity level should be documented by professionals to identify risk patients early and support them with optimal (exercise) therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Schulz, Bizjak, Moebes, John, Wais, Bunjes, Sala, Steinacker and Kirsten.)

Introduction: COVID-19 is a multi-systemic disease which can target the lungs and the cardiovascular system and can also affect parts of the brain for prolonged periods of time. Even healthy athletes without comorbidities can be psychologically affected long-term by COVID-19., Objective: This study aimed to investigate athletes' perceived mental stress and recovery levels in daily life, and their maximal aerobic power, at three different time points, post COVID-19., Methods: In total, 99 athletes (62.6% male), who had been infected by COVID-19, filled out the Recovery Stress Questionnaire for Athletes (REST-Q-Sport) and completed cardiopulmonary exercise testing (endpoint maximal aerobic power output (Pmax)) at the initial screening (t1: 4 months after infection). Follow-up assessments occurred three (t2, n = 37) and seven months after t1 (t3, n = 19)., Results: Subgroup means from the Recovery category were significantly below the reference value of four at all three time points, except "General Recovery" (3.76 (± 0.96), p = 0.275, d = 0.968) at t3."Overtiredness" (2.34 (± 1.27), p = 0.020, r = 0.224) was significantly above the reference value of two at t1, while all other Stress subgroups were not significantly different from the reference value or were significantly below the maximum threshold of two at t1, t2 and t3. Spearman's ρ revealed a negative association between Pmax and the subcategories of stress (ρ = -0.54 to ρ = -0.11, p < 0.050), and positive correlations between Pmax and "Somatic Recovery" (ρ = 0.43, p < 0.001) and "General Recovery" (ρ = 0.23, p = 0.040) at t1. Pmax (t1: 3.83 (± 0.99), t2: 3.78 (± 1.14), β = 0.06, p < 0.003) increased significantly from t1 to t2. In addition, REST-Q-Sport indicated a decrease in "Sleep" (t2 = 2.35 (± 0.62), t3 = 2.28(± 0.61), β = -0.18, p < 0.023) at t3, when compared to t2., Conclusion: The perceived recovery seems to be negatively affected in post COVID-19 athletes. Physical performance post COVID-19 correlates with both "Emotional and Somatic Stress" and "Somatic and General Recovery", indicating potential mental and physical benefits of exercise. While it is evident that COVID-19, like other viral infections, may have an influence on physical performance, monitoring stress and recovery perceptions of athletes is critical to facilitate their return-to-sports, while minimizing long-term COVID-19 induced negative effects like the athletic objective and subjective perceived recovery and stress levels., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zorn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

β2-agonists are used for the treatment of bronchoconstriction, but also abused in doping. Beside an ergogenic activity β2-agonists may have also anabolic activity. Therefore, we investigated the anabolic activity and associated molecular mechanisms of Salbutamol (SAL) and Formoterol (FOR) alone, as well as in combination in C2C12 myotubes. In differentiated C2C12 cells, dose-dependent effects of SAL and FOR (alone/in combination) on myotube diameter, myosin heavy chain (MHC) protein expression and the mRNA expression of genes involved in hypertrophy were analyzed. β2-adrenoceptor 2 (ADRB2), androgen receptor (AR) and estrogen receptor (ER) inhibitors, as well as dexamethasone (Dexa) were co-incubated with the β2-agonists and myotube diameter was determined. SAL and FOR treatment significantly induced hypertrophy and increased MHC expression and the mRNA expression of Igf1, mTOR, PIk3r1 and AMpKa2. In contrast to an ER inhibitor, the ADRB2 and AR inhibitors, as well as Dexa antagonized FOR and SAL induced hypertrophy. Combined treatment with SAL and FOR resulted in significant additive effects on myotube diameter and MHC expression. Future clinical studies are needed to prove this effect in humans and to evaluate this finding with respect to antidoping regulations., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Patrick Diel reports financial support was provided by World Anti-Doping Agency., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: After the acute Sars-CoV-2-infection, some athletes suffer from persistent, performance-impairing symptoms, although the course of the disease is often mild to moderate. The relation between cardiopulmonary performance and persistent symptoms after the acute period is still unclear. In addition, information about the development of this relationship is lacking., Objective: To assess the prevalence of persistent symptoms over time and their association with the performance capability of athletes., Methods: We conducted two cardiopulmonary exercise tests (CPET) in a three months interval with 60 athletes (age: 35.2±12.1 years, 56.7% male) after infection with Sars-CoV-2 (t0: study inclusion; t1: three months post t0). At each examination, athletes were asked about their persistent symptoms. To evaluate the change of Peak VO2/BM (Body Mass) between the time before infection and the first examination, the VO2/BM (predVO2) before infection was predicted based on anthropometric data and exercise history of the athletes. For data analysis, athletes were grouped according to their symptom status (symptom-free, SF; persistent symptoms, PS) and its progression from the first to the second examination 1) SF-SF, 2) PS-SF and 3) PS-PS., Results: Comparing the SF and PS groups at t0, significant differences for Max Power/BM, Max Power/lbm (lean body mass), Peak VO2, Peak VO2/BM, Peak VO2/lbm, Peak VO2/HR, Peak VE, Peak Vt and VE/VCO2-Slope were observed. Regarding the progression over three months, an increase in Max Power/BM was shown in SF-SF and PS-SF (tendency). Max Power/lbm increased in SF-SF and PS-PS (tendency). A decrease of VE/VCO2-Slope in PS-PS was found., Conclusion: COVID-19 led to a decline in performance that was greater in PS than in SF. Additionally, PS had decreased ventilatory parameters compared to SF. Furthermore, an improvement over time was observed in some CPET parameters and a partial recovery was observed judging by the decrease in various symptoms., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Vollrath et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Hematological and hemorheological parameters are known to be altered in COVID-19; however, the value of combined monitoring in order to deduce disease severity is only scarcely examined. A total of 44 acute SARS-CoV-2-infected patients (aCOV) and 44 age-matched healthy controls (Con) were included. Blood of aCOV was sampled at admission (T0), and at day 2 (T2), day 5 (T5), day 10 (T10), and day 30 (T30) while blood of Con was only sampled once. Inter- and intra-group differences were calculated for hematological and hemorheological parameters. Except for mean cellular volume and mean cellular hemoglobin, all blood cell parameters were significantly different between aCOV and Con. During the acute disease state (T0-T5), hematological and hemorheological parameters were highly altered in aCOV; in particular, anemic conditions and increased immune cell response/inflammation, oxidative/nitrosative stress, decreased deformability, as well as increased aggregation, were observed. During treatment and convalescence until T30, almost all abnormal values of aCOV improved towards Con values. During the acute state of the COVID-19 disease, the hematological, as well as the hemorheological system, show fast and potentially pathological changes that might contribute to the progression of the disease, but changes appear to be largely reversible after four weeks. Measuring RBC deformability and aggregation, as well as oxidative stress induction, may be helpful in monitoring critically ill COVID-19 patients.

Moderate endurance exercise leads to an improvement in cardiovascular performance, stress resilience, and blood function. However, the influence of chronic endurance exercise over several hours or days is still largely unclear. We examined the influence of a non-stop 160.9/230 km ultramarathon on body composition, stress/cardiac response, and nutrition parameters. Blood samples were drawn before (pre) and after the race (post) and analyzed for ghrelin, insulin, irisin, glucagon, cortisol, kynurenine, neopterin, and total antioxidant capacity. Additional measurements included heart function by echocardiography, nutrition questionnaires, and body impedance analyses. Of the 28 included ultra-runners (7f/21m), 16 participants dropped out during the race. The remaining 12 finishers (2f/10m) showed depletion of antioxidative capacities and increased inflammation/stress (neopterin/cortisol), while energy metabolism (insulin/glucagon/ghrelin) remained unchanged despite a high negative energy balance. Free fat mass, protein, and mineral content decreased and echocardiography revealed a lower stroke volume, left end diastolic volume, and ejection fraction post race. Optimizing nutrition (high-density protein-rich diet) during the race may attenuate the observed catabolic and inflammatory effects induced by ultramarathon running. As a rapidly growing discipline, new strategies for health prevention and extensive monitoring are needed to optimize the athletes' performance.

Introduction: In patients with SARS-CoV-2, innate immunity is playing a central role, depicted by hyperinflammation and longer lasting inflammatory response. Reliable inflammatory markers that cover both acute and long-lasting COVID-19 monitoring are still lacking. Thus, we investigated one specific inflammatory marker involved as one key player of the immune system, kynurenine (Kyn), and its use for diagnosis/detection of the Long-/Post-COVID syndrome in comparison to currently used markers in both serum and saliva samples., Material and Methods: The study compromised in total 151 inpatients with a SARS-CoV-2 infection hospitalized between 03/2020 and 09/2021. The group NC (normal controls) included blood bank donors (n=302, 144f/158m, mean age 47.1 ± 18.3 years (range 18-75)). Two further groups were generated based on Group A (n=85, 27f/58m, mean age 63.1 ± 18.3 years (range 19-90), acute admission to the hospital) and Group B (n=66, 22f/44m, mean age 66.6 ± 17.6 years (range 17-90), admitted either for weaning or for rehabilitation period due to Long-COVID symptoms/syndrome). Plasma concentrations of Kyn, C-Reactive Protein (CRP) and interleukin-6 (IL-6) were measured on admission. In Group B we determined Kyn 4 weeks after the negative PCR-test. In a subset of patients (n=11) concentrations of Kyn and CRP were measured in sera and saliva two, three and four months after dismission. We identified 12 patients with Post-COVID symptoms >20 weeks with still significant elevated Kyn-levels., Results: Mean values for NC used as reference were 2.79 ± 0.61 µM, range 1.2-4.1 µM. On admission, patients showed significantly higher concentrations of Kyn compared to NC (p-values < 0.001). Kyn significantly correlated with IL-6 peak-values (r=0.411; p-values <0.001) and CRP (r=0.488, p-values<0.001). Kyn values in Group B (Long-/Post-COVID) showed still significant higher values (8.77 ± 1.72 µM, range 5.5-16.6 µM), whereas CRP values in Group B were in the normal range., Conclusion: Serum and saliva Kyn are reflecting the acute and long-term pathophysiology of the SARS-CoV-2 disease concerning the innate immune response and thus may serve a useful biomarker for diagnosis and monitoring both Long- and Post-COVID syndrome and its therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bizjak, Stangl, Börner, Bösch, Durner, Drunin, Buhl and Abendroth.)

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 (⩒O 2peak ) 12%-improved POST ( p  = 0.05) and declined to baseline values T24, while CG ⩒O 2peak 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.

Background and Aim: Childhood obesity is an emerging problem often leading to earlier onset of non-communicable diseases in later life. Biomarkers to identify individual risk scores are insufficient in routine clinical practice, which is related to the need for easily sampled, non-invasive survey methods in children. We aimed to investigate and strengthen possible pro-inflammatory markers and epigenetic risk factors in saliva of obese children compared to lean controls., Methods and Results: 19 overweight/obese (OC, 10.1 ± 1.9 years, BMI 27.7 ± 3.2 kg/m 2 ) and 19 lean control children (CC, 9.7 ± 2.5 years, BMI 16.4 ± 1.8 kg/m 2 ) participated in this explorative pilot study. Anthropometric measures, saliva and cheek swab samples were taken. Saliva profiles were examined for acute phase proteins (CRP and neopterin) and pro-inflammatory cytokines (IL-17a/IL-1β/IL-6). Cheek swabs were analyzed to investigate DNA methylation differences with subsequent hierarchical cluster and principal component analyses (PCA). Saliva analysis showed significant increased CRP concentrations in OC compared to CC (p < 0.001). There were no significant differences, but high intra-individual values in neopterin, IL-17a, IL-1β and IL-6. An unsupervised PCA of CpG loci with high variance (σ/σ max  > 0.2) clearly separated OC and CC according to their methylation pattern. Furthermore, a supervised approach revealed 7125 significantly differentially methylated loci, whose corresponding genes were significantly enriched for genes playing roles in e.g., cellular signalling, cytoskeleton organization and cell motility., Conclusions: CRP and methylation status determinations in saliva are suitable as non-invasive methods for early detection of risks for non-communicable diseases in children/adolescents and might be a useful supplementary approach in the routine clinical practice/monitoring., Competing Interests: Declaration of competing interest No conflict of interest to disclosure., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Metabolic stress is high during training and competition of Olympic rowers, but there is a lack of biomedical markers allowing to quantify training load on the molecular level. We aimed to identify such markers applying a complex approach involving inflammatory and immunologic variables. Methods: Eleven international elite male rowers (age 22.7 ± 2.4 yrs.; VO 2 max 71 ± 5 ml·min -1 ·kg -1 ) of the German National Rowing team were monitored at competition phase (COMP) vs. preparation phase (PREP), representing high vs. low load. Perceived stress and recovery were assessed by a Recovery Stress Questionnaire for Athletes ( RESTQ-76 Sport ). Immune cell activation (dendritic cell (DC)/macrophage/monocytes/T-cells) was evaluated via fluorescent activated cell sorting. Cytokines, High-Mobility Group Protein B1 (HMGB1), cell-free DNA (cfDNA), creatine kinase (CK), uric acid (UA), and kynurenine (KYN) were measured in venous blood. Results: Rowers experienced more general stress and less recovery during COMP, but sports-related stress and recovery did not differ from PREP. During COMP, DC/macrophage/monocyte and T-regulatory cells (T reg -cell) increased ( p  = 0.001 and 0.010). HMGB1 and cfDNA increased in most athletes during COMP ( p  = 0.001 and 0.048), while CK, UA, and KYN remained unaltered ( p  = 0.053, 0.304, and 0.211). Pro-inflammatory cytokines IL-1β ( p  = 0.002), TNF-α ( p  < 0.001), and the chemokine IL-8 ( p  = 0.001) were elevated during COMP, while anti-inflammatory Il-10 was lower ( p  = 0.002). Conclusion: COMP resulted in an increase in biomarkers reflecting tissue damage, with plausible evidence of immune cell activation that appeared to be compensated by anti-inflammatory mechanisms, such as T reg -cell proliferation. We suggest an anti-inflammatory and immunological matrix approach to optimize training load quantification in elite athletes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bizjak, Treff, Zügel, Schumann, Winkert, Schneider, Abendroth and Steinacker.)

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 (VO 2 peak). 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 (VO 2 T1) did not differ between groups. There were positive associations between VO 2 peak and VO 2 VT1 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/VO 2 peak 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., (© 2021. The Author(s).)

Background: Asthma and/or airway hyper-responsiveness (AHR) are common in elite endurance athletes with a high prevalence rate of beta-2 adrenoreceptor (beta-2) agonists use. Nevertheless, there are data on dose-dependent ergogenic effects of beta-2 agonists suggesting increased muscle strength, endurance and neuromuscular performance. Therefore, most beta-2 agonists belong to the World Anti Doping Agency (WADA) list of prohibited substances and it is tempting to speculate that illegitimate use of beta-2 agonists might be a common practice to boost performance in competitive sports. It is currently unknown whether or not inhaled beta-2 agonists enhance performance by stimulatory effects in skeletal and cardiac muscle., Methods: The ELSA trial is a double-blinded, placebo-controlled, randomized, balanced, four-way cross-over study. Study participants (n=24, 12 ♀, 12 ♂) complete four study arms (i.e. periods with treatment A, placebo; B, salbutamol; C, formoterol; D, formoterol + salbutamol) in random order after an initial preliminary testing session. Participants inhale the study medication 20 min before the 10-min time trial (TT; exercise performance test), where participants cycle 10 min at the highest possible workload. Cardiac output is measured continuously. A skeletal muscle biopsy is collected 3 h after the TT. Study endpoints include measures of skeletal muscle expression of nuclear receptors, hormones and cytokine levels, urinary and plasma concentrations of salbutamol and formoterol, circulating cardiac markers, cardiopulmonary function and exercise performance (average power and peak power during the TT). Blood and urine are collected and respiratory testing is performed 24 h post TT. This clinical trial evaluates the potential performance-enhancing effects of non-prohibited, not medically indicated inhaled short- and long-acting beta-2 agonists on skeletal muscle gene expression, endocrine regulation, cardiac biomarkers, cardiopulmonary function and acute endurance exercise performance. These data will be used by WADA to adapt the annually published list of prohibited substances (WADA 2021) and will be published in scientific journals., Trial Registration: The trial is registered at the European Clinical Trials Database (Eudra CT) with the number: 2015-005598-19 as well as at the German register for clinical studies (DRKS number 00010574 )., (© 2021. The Author(s).)

The aim of this study was to investigate differences in skeletal muscle gene expression of highly trained endurance and strength athletes in comparison to untrained individuals at rest and in response to either an acute bout of endurance or strength exercise. Endurance (ET, n = 8, VO 2 max 67 ± 9 mL/kg/min) and strength athletes (ST, n = 8, 5.8 ± 3.0 training years) as well as untrained controls (E-UT and S-UT, each n = 8) performed an acute endurance or strength exercise test. One day before testing (Pre), 30 min (30'Post) and 3 h (180'Post) afterwards, a skeletal muscle biopsy was obtained from the m. vastus lateralis. Skeletal muscle mRNA was isolated and analyzed by Affymetrix-microarray technology. Pathway analyses were performed to evaluate the effects of training status (trained vs. untrained) and exercise mode-specific (ET vs. ST) transcriptional responses. Differences in global skeletal muscle gene expression between trained and untrained were smaller compared to differences in exercise mode. Maximum differences between ET and ST were found between Pre and 180'Post. Pathway analyses showed increased expression of exercise-related genes, such as nuclear transcription factors (NR4A family), metabolism and vascularization (PGC1-α and VEGF-A), and muscle growth/structure (myostatin, IRS1/2 and HIF1-α. The most upregulated genes in response to acute endurance or strength exercise were the NR4A genes (NR4A1, NR4A2, NR4A3). The mode of acute exercise had a significant effect on transcriptional regulation Pre vs. 180'Post. In contrast, the effect of training status on human skeletal muscle gene expression profiles was negligible compared to strength or endurance specialization. The highest variability in gene expression, especially for the NR4A-family, was observed in trained individuals at 180'Post. Assessment of these receptors might be suitable to obtain a deeper understanding of skeletal muscle adaptive processes to develop optimized training strategies.

Objective: To examine the impact of a 6-week endurance training on red blood cell (RBC) aging and deformability of healthy participants to detect possible improved hemorheological and performance-related adaptations., Methods: A total of 31 participants (17 females and 14 males) performed a 6-week moderate training protocol (three 1-h running sessions per week at 70% of maximal heart rate). Blood was sampled before and after the training. RBCs from each participant were fractioned according to density and age into 4 RBC subfractions. Subfractions were examined for changes of RBC properties, including aging distribution, RBC deformability, RBC microparticles, and phosphatidylserine concentrations. RBC and plasma nitrite levels were measured as indicators of nitric oxide metabolism., Results: Aerobic performance, peak oxygen consumption, ventilatory thresholds, velocity at the aerobic-anaerobic threshold, and lactate at exhaustion improved after training. The relative amount of both young RBCs and old RBCs increased, and the amount of the main RBC fraction decreased. Phosphatidylserine externalization and RBC-derived microparticles decreased. Overall deformability expressed as shear stress required to achieve half-maximum deformation to theoretical maximal elongation index at infinite shear stress improved in unfractioned RBCs (p < 0.001). Nitrite decreased in total (p = 0.001), young (p < 0.001), main (p < 0.001), and old (p = 0.020) aged RBCs and in plasma (p = 0.002), but not in very old RBCs., Conclusion: These results indicate that non-endurance-trained healthy participants benefit from a regular moderate running training program because performance-related parameters improve and a younger RBC population with improved RBC properties is induced, which might support oxygen supply in the microcirculation., (Copyright © 2019. Production and hosting by Elsevier B.V.)

: 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 (VO 2 peak) and 1-repetition maximum (1-RM) at six different training machines. VO 2 peak 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., Competing Interests: The authors declare no conflict of interest.

Recent technological developments provide easy access to use an artificial oxygen supply (hyperoxia) during exercise training. The aim of this study was to assess the efficacy of a commercially available oxygen compressor inducing low-dose hyperoxia, on limiting factors of endurance performance. Thirteen active men (age 24 ± 3 years) performed a high-intensity interval exercise (HIIE) session (5 × 3 min at 80% of W max , separated by 2 min at 40% W max ) on a cycle ergometer, both in hyperoxia (4 L∙min -1 , 94% O 2 , HYP) or ambient conditions (21% O 2 , NORM) in randomized order. The primary outcome was defined as red blood cell deformability (RBC-D), while our secondary interest included changes in muscle oxygenation. RBC-D was expressed by the ratio of shear stress at half-maximal deformation (SS 1 / 2 ) and maximal deformability (EI max ) and muscle oxygenation of the rectus femoris muscle was assessed by near-infrared spectroscopy. No statistically significant changes occurred in SS 1 / 2 and EI max in either condition. The ratio of SS 1 / 2 to EI max statistically decreased in NORM ( p < 0.01; Δ: -0.10; 95%CI: -0.22, 0.02) but not HYP ( p > 0.05; Δ: -0.16; 95%CI: -0.23, -0.08). Muscle oxygenation remained unchanged. This study showed that low-dose hyperoxia during HIIE using a commercially available device with a flow rate of only 4 L·min -1 may not be sufficient to induce acute ergogenic effects compared to normoxic conditions.

Background: Autologous blood doping (ABD) is applied to improve performance capacity. ABD includes blood donation, red blood cell (RBC) storage at -80°C and re-infusion prior to or during competition. ABD is not directly detectable with current detection techniques., Objective: Since cryopreservation is known to affect RBC physiology in vitro, the aim of the study was to examine whether these alterations are detectable in vivo., Methods: Blood from six healthy male donors was transferred into conventional blood bags, cryopreserved, stored for 18 weeks at -80°C and re-infused with a RBC volume corresponding to ∼4% of total blood volume into respective donor. RBC physiology parameters were measured before blood donation/re-infusion, and 0/1/2/6/24/48/72 h and 1 w post re-infusion., Results: RBC parameters and age markers were unaffected during intervention. RBC deformability increased from pre-blood-sampling to pre-re-infusion while deformability and viscosity values remained unaltered post re-infusion. RBC nitric oxide associated analytes, metabolic parameters and electrolyte concentrations remained unaffected., Conclusions: The data of this pilot study indicate that the increase in RBC deformability might be related to neoformation of RBC after blood donation. The lack of changes in tested parameters might be related to the low re-infused RBC volume which might explain differences to in vitro results.

Patients with sickle cell anemia (SCA) show impaired ventilatory efficiency, altered blood rheology, high levels of oxidative/nitrosative stress and enhanced hemolysis with large amounts of circulating free hemoglobin, which reduces nitric oxide (NO) bioavailability. The aim of the study was to investigate whether physical exercise could improve these physiological and biological markers described to contribute to SCA pathophysiology. Twelve SCA patients participated in a controlled six weeks training program with moderate volume (two sessions per week with 15-30 min duration per session) and intensity (70% of the first ventilatory threshold). Parameters were compared before (T0) and after (T1) training. Daily activities were examined by a questionnaire at T0 and one year after the end of T1. Results revealed improved ventilatory efficiency, reduced nitrosative stress, reduced plasma free hemoglobin concentration, increased plasma nitrite levels and altered rheology at T1 while no effect was observed for exercise performance parameters or hematological profile. Red blood cell (RBC) NO parameters indicate increased NO bioavailability which did not affect RBC deformability. Participants increased their daily life activity level. The data from this pilot study concludes that even low intensity activities are feasible and could be beneficial for the health of SCA patients., Competing Interests: The authors declare no conflict of interest.

Background: The Fontan circulation is a unique palliation procedure for several congenital heart defects. Impaired exercise capacity has previously been demonstrated in these patients and also a higher risk for cardiopulmonary mortality. Hemorheology was shown to affect cardiopulmonary capacity and in turn to be affected by regular exercise and hypoxia but none of these have been investigated in Fontan patients so far. The aim of this study was to detect general differences in hemorheology in normoxia as well as possible altered hemorheological responses to hypoxia exposure and hypoxic exercise between Fontan patients and healthy controls., Methods and Findings: 26 Fontan patients and 20 healthy controls performed an acute exercise test (AET) on a bicycle ergometer under hypoxia with ambient 15.2% oxygen saturation (sO 2 ). Blood samples were taken at rest in normoxia (T0), at rest in hypoxia (T1), after maximum exhaustion in hypoxia (T2), and after 50 min recovery in normoxia (T3). Hemorheological and blood parameters were investigated. Additionally, arterial stiffness was tested at T0. Red blood cell (RBC) deformability, NOx, erythropoietin (EPO) concentration, RBC count, hemoglobin (Hb) concentration and hematocrit (hct) were significantly increased in Fontan patients compared to controls. Same was observed for arterial stiffness. No changes were observed for RBC aggregation, fibrinogen concentration, free radical levels and vascular endothelial growth factor (VEGF). Hypoxia exposure did not change parameters, whereas exercise in hypoxia increased aggregation and hct significantly in both groups. Fontan patients showed significantly increased aggregation-disaggregation balance compared to controls., Conclusion: Acute hypoxia exposure and exercise under hypoxia might have similar impact on hemorheology in Fontan patients and controls and was clinically well tolerated. Nevertheless, exercise alters aggregation and possibly hemodynamics which requires special attention in Fontan patients., (Copyright © 2019 Härtel, Müller, Herberg, Breuer, Bizjak, Bloch and Grau.)

Aim: To investigate the influence of the intranasal AlaxoLito Plus Nasal Stent during exercise on nitric oxide (NO) synthesis, NO exhalation, red blood cell (RBC) deformability and oxygen uptake., Methods: Parameters were measured before and after acute cycle ergometer test at different intensities. Spirometric, microrheological and NO parameters were determined for oral (OB), nasal (NB) and nasal-stent breathing (SB). RBC deformability was measured and elongation indices for 3.87 Pa and maximal deformability were calculated. RBC/plasma/exhaled NO, oxygen uptake and respiratory rate were determined., Results: Exhaled NO was higher at rest during OB compared to SB and NB and decreased after exercise with NB and SB. Plasma and RBC NO remained unaltered during intervention. RBC deformability increased at moderate intensity during SB. Deformability decreased at moderate and medium intensity with NB. Respiratory rate for same oxygen uptake did not differ between breathing settings., Conclusion: The AlaxoLito Plus Nasal Stent may modulate deformability during moderate exercise and increase NO exhalation without major effects on oxygen uptake and performance., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Sickle cell anaemia (SCA) is characterized by reduced red blood cell (RBC) deformability and nitric oxide (NO) bioavailability. The aim of the study was to investigate whether exercise might affect these parameters in SCA. SCA patients and healthy controls (AA) performed an acute submaximal exercise test until subjects reached the first ventilatory threshold (VT 1). Blood was sampled at rest and at VT 1. At rest, free haemoglobin level was higher and RBC count, haemoglobin and haematocrit were lower in SCA compared to AA. RBC deformability was lower in SCA. Exercise had no effect on the tested parameters. RBC NO level was higher in SCA compared to AA at rest and significantly decreased after exercise in SCA. This might be related to a reduction in RBC-NO synthase (RBC-NOS) activation which was only observed in SCA after exercise. Free radical levels were higher in SCA at rest but concentration was not affected by exercise. Marker for lipid peroxidation and antioxidative capacity were similar in SCA and AA and not affected by exercise. In conclusion, a single acute submaximal bout of exercise has no deleterious effects on RBC deformability or oxidative stress markers in SCA, and seems to modulate RBC-NOS signalling pathway.

Physical performance and regeneration after exercise is enhanced by the ingestion of proteins and carbohydrates. These nutrients are generally consumed by athletes via whey protein and glucose-based shakes. In this study, effects of protein and carbohydrate on skeletal muscle regeneration, given either by shake or by a meal, were compared. 35 subjects performed a 10 km run. After exercise, they ingested nothing (control), a protein/glucose shake (shake) or a combination of white bread and sour milk cheese (food) in a randomized cross over design. Serum glucose ( n = 35), serum insulin ( n = 35), serum creatine kinase ( n = 15) and myoglobin ( n = 15), hematologic parameters, cortisol ( n = 35), inflammation markers ( n = 27) and leg strength ( n = 15) as a functional marker were measured. Insulin secretion was significantly stimulated by shake and food. In contrast, only shake resulted in an increase of blood glucose. Food resulted in a decrease of pro, and stimulation of anti-inflammatory serum markers. The exercise induced skeletal muscle damage, indicated by serum creatine kinase and myoglobin, and exercise induced loss of leg strength was decreased by shake and food. Our data indicate that uptake of protein and carbohydrate by shake or food reduces exercise induced skeletal muscle damage and has pro-regenerative effects.

Aim: High glycerol cryopreservation of red blood cells (RBCs) reduces metabolic processes at ultralow temperatures but less is known regarding the effect of cryopreservation on RBC nitric oxide (NO) metabolism, haemorheological properties, structural behaviour and membrane fragility., Methods: Blood from ten healthy participants was sampled, glycerolized and stored at -80 °C (SB). Aliquots were thawed and further processed after 4, 8 and 12 weeks, respectively. At these time points, fresh blood (FB) was additionally sampled from each participant. FB/SB mixtures were prepared corresponding to transfusion of 1-3 blood bags. Additionally, mixtures were exposed to shear stress similar to that found in the circulation and deformability was measured to estimate possible behaviour of cryopreserved RBC in vivo., Results: Ageing of RBC was reduced during cryopreservation. Markers for RBC metabolism (ATP, 2,3-DPG) were not altered but RBC sodium levels increased and potassium and calcium decreased, respectively. Mean cellular volume was higher and accordingly, mean cellular haemoglobin concentration was lower in SB. Deformability was altered during storage with less shear stress necessary to deform RBCs. Changes were also detectable in blood mixtures. Deformability remained unaltered in shear stress settings in FB and SB. RBC viscosity was reduced in SB. RBC-NOS content and phosphorylation sites as well as nitrite and RxNO levels seem not to be affected by the intervention., Conclusion: Cryopreservation maintains RBC metabolic function in vitro, but structure and function of cryopreserved RBC seems to be altered. Impact of these alterations in vivo seems to be less but needs further investigation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Depending on the exercise variables and training design, resistance exercise can be applied to gain muscle mass, prevent diseases like osteoporosis and sarcopenia or generally increase strength capacity. But the influence on blood flow parameters and possible consequences in health and disease are less understood. To examine the possible impact of resistance exercise of different duration on hemorheology, oxidative stress and microvascular function, participants (n = 6) performed lower-limb resistance exercise of the quadriceps femoris. Loading consisted of 1 (S1), 5 (S5) and 10 (S10) sets, on separated days, at the individual 10 repetition maximum. Blood samples were taken before (Pre) and after (Post0) each set as well after a 25-min recovery period (Post25). Hemograms were measured to analyze hematocrit, white blood cell (WBC) count and red blood cell (RBC) count. RBC deformability and aggregation were measured by ektacytometry and syllectometry to determine hemorheological responses. Plasma and RBC nitrate were measured by chemiluminescence detection to determine nitric oxide production. Formation of N-tyrosine and plasma malondialdehyde to determine oxidative stress and lipid peroxidation were measured by immunostaining and ELISA, respectively. Hematocrit, RBC, WBC count and aggregation increased Post0 in each protocol with subsequently decreased values Post25 below Pre values. High effect size was observed regarding deformability during the different sets. RBC nitrite analysis revealed effect size alterations between the trainings, whereas plasma nitrite was not affected. Effects size was evident in lipid peroxidation, whereas N-tyrosine concentration was not altered. Lower-limb resistance exercise induced acute changes in hematological and hemorheological parameters, whereby intermittent hemodilution and plasma shifts seemed the major contributor. The acute adaptations of RBC function seen during short duration resistance exercise might contribute to beneficial effects on microvascular circulation with a low oxidative stress response., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study examines the effects of endurance training on red blood cells (RBC) in seventeen non-insulin-dependent type 2 diabetic men with a special focus on in vivo RBC aging. Venous blood was collected pre- and post-training at rest. RBC from whole blood and RBC separated according to cell age by density-gradient centrifugation were analyzed. RBC deformability was measured by ektacytometry. Immunohistochemical staining was performed to quantify the RBC-nitric oxide (NO) synthase activation (RBC-NOSSer1177) because RBC-NOS-produced NO can contribute to increased RBC deformability. The proportion of "young" RBC was significantly higher post-training. RBC deformability of all RBC (RBC of all ages) remained unaltered post-training. During RBC aging, RBC deformability decreased in both pre- and post-training. However, the training significantly increased RBC deformability in "young" and reduced their deformability in aging RBC. RBC-NOS activation remained unaltered in all RBC post-training. It tendentially increased in aging RBC pre-training, but did not change during aging post-training. The training significantly reduced RBC-NOS activation in "old" RBC. Endurance training may improve the RBC system (higher amount of "young" RBC which are more deformable). It remains speculative whether changes in older RBC (reduced RBC-NOS activation and deformability) could lead to more rapid elimination of aged RBC.

The red-vine-leaf extract AS195 improves cutaneous oxygen supply and the microcirculation in patients suffering from chronic venous insufficiency. Regulation of blood flow was associated to nitric oxide synthase (NOS)-dependent NO (nitric oxide) production, and endothelial and red blood cells (RBC) have been shown to possess respective NOS isoforms. It was hypothesized that AS195 positively affects NOS activation in human umbilical vein endothelial cells (HUVECs) and RBC. Because patients with microvascular disorders show increased oxidative stress which limits NO bioavailability, it was further hypothesized that AS195 increases NO bioavailability by decreasing the content of reactive oxygen species (ROS) and increasing antioxidant capacity. Cultured HUVECs and RBCs from healthy volunteers were incubated with AS195 (100 μmol/L), tert-butylhydroperoxide (TBHP, 1 mmol/L) to induce oxidative stress and with both AS195 and TBHP. Endothelial and red blood cell-nitric oxide synthase (RBC-NOS) activation significantly increased after AS195 incubation. Nitrite concentration, a marker for NO production, increased in HUVEC but decreased in RBC after AS195 application possibly due to nitrite scavenging potential of flavonoids. S-nitrosylation of RBC cytoskeletal spectrins and RBC deformability were increased after AS195 incubation. TBHP-induced ROS were decreased by AS195, and antioxidative capacity was significantly increased in AS195-treated cells. TBHP also reduced RBC deformability, but reduction was attenuated by parallel incubation with AS195. Adhesion of HUVEC was also reduced after AS195 treatment. Red-vine-leaf extract AS195 increases NOS activation and decreases oxidative stress. Both mechanisms increase NO bioavailability, improve cell function, and may thus account for enhanced microcirculation in both health and disease.

Aim: To investigate RBC-NOS dependent NO signaling during in vivo RBC aging in health and disease., Method: RBC from fifteen healthy volunteers (HC) and four patients with type 2 diabetes mellitus (DM) were separated in seven subpopulations by Percoll density gradient centrifugation., Results: The proportion of old RBC was significantly higher in DM compared to HC. In both groups, in vivo aging was marked by changes in RBC shape and decreased cell volume. RBC nitrite, as marker for NO, was higher in DM and increased in both HC and DM during aging. RBC deformability was lower in DM and significantly decreased in old compared to young RBC in both HC and DM. RBC-NOS Serine1177 phosphorylation, indicating enzyme activation, increased during aging in both HC and DM. Arginase I activity remained unchanged during aging in HC. In DM, arginase I activity was significantly higher in young RBC compared to HC but decreased during aging. In HC, concentration of L-arginine, the substrate of RBC-NOS and arginase I, significantly dropped from young to old RBC. In DM, L-arginine concentration was significantly higher in young RBC compared to HC and significantly decreased during aging. In blood from healthy subjects, RBC-NOS activation was additionally inhibited by N5-(1-iminoethyl)-L-Ornithine dihydrochloride which decreased RBC nitrite, and impaired RBC deformability of all but the oldest RBC subpopulation., Conclusion: This study first-time showed highest RBC-NOS activation and NO production in old RBC, possibly to counteract the negative impact of cell shrinkage on RBC deformability. This was even more pronounced in DM. It is further suggested that highly produced NO only insufficiently affects cell function of old RBC maybe because of isolated RBC-NOS in old RBC thus decreasing NO bioavailability. Thus, increasing NO availability may improve RBC function and may extend cell life span in old RBC.