Letter to the editor: fasting decreases expression of microRNAs linked to endothelial pathophysiology in mononuclear cells of healthy subjects.

This study explores how 14-15 h fasting or acute exercise affects immune cell epigenetics, specifically focusing on miRNAs in mononuclear cells. Findings suggest fasting significantly impacts microRNAs associated with endothelial metabolism compared to exercise, but does not directly connect these changes to cell apoptosis or autophagy. This enhances comprehension of cellular self-consumption under health-promoting interventions.

Circulating Gal-3 and sST2 are associated with acute exercise-induced sustained endothelial activation: Possible relevance for fibrosis development?

Long-term, intense endurance exercise training can occasionally induce endothelial micro-damage and cardiac fibrosis. The underlying mechanisms are incompletely understood. Twenty healthy, well-trained male participants (10 runners and 10 cyclists) performed a strenuous high-intensity interval training (HIIT) session matched by age, height, weight and maximal oxygen consumption. We assessed the acute exercise response of novel cardiac biomarkers of fibrosis [e.g., galectin-3 (Gal-3) and soluble suppression of tumorigenicity 2 (sST2)] per exercise modality and their relationship with haemodynamic contributors, such as preload, afterload and cardiac contractility index (CTi), in addition to endothelial damage by sustained activation and shedding of endothelial cells (ECs). Serum Gal-3 and sST2 concentrations were investigated by enzyme-linked immunosorbent assays; haemodynamics were analysed via impedance plethysmography and circulating ECs by flow cytometry. The Gal-3 and sST2 concentrations and ECs were elevated after exercise (P < 0.001), without interaction between exercise modalities. Circulating Gal-3 and sST2 concentrations both showed a positive relationship with ECs (rrm  = 0.68, P = 0.001 and rrm  = 0.57, P = 0.010, respectively, both n = 18). The EC association with Gal-3 was significant only in cyclists, but equally strong for both modalities. Gal-3 was also related to exercise-induced CTi (rrm  = 0.57, P = 0.011, n = 18). Cardiac wall stress is increased after an acute HIIT session but does not differ between exercise modalities. Exercise-released Gal-3 from cardiac macrophages could very probably drive systemic endothelial damage, based on an enhanced CTi. The importance of acute exercise-induced vascular resistances and cardiac contractility for the release of fibrotic biomarkers and any long-term pathological endothelial adaptation should be investigated further, also relative to the exercise modality. NEW FINDINGS: What is the central question of this study? Circulating biomarkers of cardiac wall stress and fibrosis are influenced by physical exercise. The underlying mechanisms per exercise modality are still unclear. What is the main finding and its importance? We show that galectin-3 (Gal-3) and soluble suppression of tumorigenicity 2 (sST2) are increased after acute exercise but do not differ between running and cycling. One haemodynamic contributor to the secretion of Gal-3 is an enhanced cardiac contractility. Acute exercise-released Gal-3 and sST2 are linked to sustained endothelial activation and cell shedding. This could be relevant in the context of fibrosis development and could identify athletes at risk for pathological endothelial adaptations.

Lymphocytes are less sensitive to autophagy than monocytes during fasting and exercise conditions.

The concomitant investigation of apoptosis (a regulated cell death) and autophagy (a conserved cell survival mechanism) in immune cells is rare. More detailed knowledge of these two types of self-consumption in circulating lymphocytes and monocytes would be important, since conditions such as fasting and acute exercise could promote health by a coordinated/linked modulation of autophagy and apoptosis in these mononuclear cells. In this study we performed flow cytometry to quantify numbers of apoptotic and autophagic mononuclear cells, lymphocytes and monocytes in fasting, standardized fed, and exercise conditions, using Annexin V, LC3B, and p62, respectively. We show that within total mononuclear cells lymphocytes are less apoptotic and autophagic than monocytes during fasting (p < 0.001, p < 0.05, respectively) and after acute exercise (p < 0.01, p < 0.05, respectively). Fasting increased circulating autophagic monocyte concentrations, but not lymphocytes compared to the fed control condition. Acute exercise elevated circulating autophagic lymphocyte concentrations, but not monocytes. Interestingly, Western blotting analysis of the fasting samples showed that higher LC3BII/I ratios were correlated with lower numbers of autophagic mononuclear cells (r = - 0.74, p = 0.02, n = 8), which could be attributed to the monocyte subgroup, but not lymphocytes. These results extend the current knowledge of the two types of self-consumption in circulating immune cells and underline their possible importance in pro-inflammatory monocytes during fasting and exercise as health promoting interventions.

Microvascular endothelial dysfunction in heart failure patients: An indication for exercise treatment?

BACKGROUND: Endothelial dysfunction represents a diagnostic marker to differentiate disease severity in chronic heart failure (CHF) patients. Retinal vessel phenotyping was applied in CHF patients as it has been acknowledged as a sensitive diagnostic tool to quantify microvascular health and overall cardiovascular risk. METHODS: The central retinal arteriolar (CRAE) and venular diameter equivalents (CRVE) as well as the retinal microvascular function, quantified by arteriolar (aFID) and venular flicker-light induced dilatation (vFID), were analyzed in 26 CHF patients. These data were compared with 26 age- and sex-matched healthy peers. The effects of an exercise intervention on retinal microvascular health in one CHF patient were investigated to demonstrate potentially beneficial effects of exercise treatment in a case report format as proof of concept. RESULTS: CHF patients showed narrower CRAE (170 ± 16 µm vs. 176 ± 16 µm, p = 0.237) and wider CRVE (217 ± 20 µm vs. 210 ± 17 µm, p = 0.152), resulting in a significantly lower arteriolar-to-venular diameter ratio (AVR, 0.79 ± 0.07 vs. 0.84 ± 0.06, p = 0.004) compared to controls. More strikingly, CHF patients showed significantly lower mean aFID (1.24 ± 1.14% vs. 3.78 ± 1.85%, p < 0.001) and vFID (2.89 ± 1.33% vs. 3.88 ± 1.83%, p = 0.033). Twelve weeks of exercise therapy induced wider CRAE (143 ± 1.0 µm vs. 153 ± 0.9 µm), narrower CRVE (183 ± 3.1 µm vs. 180 ± 2.4 µm) and improved aFID (0.67% vs. 1.25%) in a male 78 years old CHF patient. CONCLUSIONS: aFID is a sensitive diagnostic tool to quantify microvascular impairments in CHF patients. Exercise treatment in CHF patients has high potential to improve retinal microvascular health as a marker for vascular regeneration and overall risk reduction, which warrants further examination by randomized controlled trials.

VascuFit: vascular effects of non-linear periodized exercise training in sedentary adults with elevated cardiovascular risk - protocol for a randomized controlled trial.

BACKGROUND: Early vascular aging (EVA) is increasingly prevalent in the general population. Exercise is important for primary cardiovascular prevention, but often insufficient due to ineffective training methods and a lack of biomarkers suitable to monitor its vascular effects. VascuFit will assess the effectiveness of non-linear periodized aerobic exercise (NLPE) in a non-athletic sedentary population to improve both established and promising biomarkers of EVA. METHODS: Forty-three sedentary adults, aged 40-60 years, with elevated cardiovascular risk will either engage in 8 weeks of ergometer-based NLPE (n = 28) or receive standard exercise recommendations (n = 15). The primary outcome will be the change of brachial-arterial flow-mediated dilation (baFMD) after versus before the intervention. Secondary outcomes will be the change in static vessel analysis (SVA; clinical biomarker of microvascular endothelial function), endomiRs (microRNAs regulating key molecular pathways of endothelial cell homeostasis) and circulating cellular markers of endothelial function (mature endothelial cells, endothelial progenitor cells). Tertiary outcomes will be the change in sphingolipidome, maximum oxygen capacity, and traditional cardiovascular risk factors (blood pressure, triglycerides, cholesterol, fasting glucose, high-sensitivity C-reactive protein). DISCUSSION: We expect an improvement of baFMD of at least 2.6% and significant pre-post intervention differences of SVA and endomiRs as well as of the tertiary outcomes in the intervention group. VascuFit may demonstrate the effectiveness of NLPE to improve endothelial function, thus vascular health, in the general sedentary population. Furthermore, this project might demonstrate the potential of selected molecular and cellular biomarkers to monitor endothelial adaptations to aerobic exercise. TRIAL REGISTRATION: The trial was registered on www. CLINICALTRIALS: gov (NCT05235958) in February 11th 2022.

Hypoxic-inflammatory responses under acute hypoxia: In Vitro experiments and prospective observational expedition trial.

Induction of hypoxia-inducible-factor-1α (HIF-1α) pathway and HIF-target genes allow adaptation to hypoxia and are associated with reduced incidence of acute mountain sickness (AMS). Little is known about HIF-pathways in conjunction with inflammation or exercise stimuli under acute hypobaric hypoxia in non-acclimatized individuals. We therefore tested the hypotheses that 1) both hypoxic and inflammatory stimuli induce hypoxic-inflammatory signaling pathways in vitro, 2) similar results are seen in vivo under hypobaric hypoxia, and 3) induction of HIF-dependent genes is associated with AMS in 11 volunteers. In vitro, peripheral blood mononuclear cells (PBMCs) were incubated under hypoxic (10%/5% O2) or inflammatory (CD3/CD28) conditions. In vivo, Interleukin 1ß (IL-1ß), C-X-C Chemokine receptor type 4 (CXCR-4), and C-C Chemokine receptor type 2 (CCR-2) mRNA expression, cytokines and receptors were analyzed under normoxia (520 m above sea level (a.s.l.)), hypobaric hypoxia (3883 m a.s.l.) before/after exercise, and after 24 h under hypobaric hypoxia. In vitro, isolated hypoxic (p = 0.004) or inflammatory (p = 0.006) stimuli induced IL-1ß mRNA expression. CCR-2 mRNA expression increased under hypoxia (p = 0.005); CXCR-4 mRNA expression remained unchanged. In vivo, cytokines, receptors, and IL-1ß, CCR-2 and CXCR-4 mRNA expression increased under hypobaric hypoxia after 24 h (all p ≤ 0.05). Of note, proinflammatory IL-1ß and CXCR-4 mRNA expression changes were associated with symptoms of AMS. Thus, hypoxic-inflammatory pathways are differentially regulated, as combined hypoxic and exercise stimulus was stronger in vivo than isolated hypoxic or inflammatory stimulation in vitro.

Anti-Mullerian hormone concentrations in individual follicular fluids within one stimulated IVF cycle resemble blood serum values.

PURPOSE: Anti-Mullerian hormone (AMH) is commonly known as the most potent marker for ovarian reserve due to its decline as female age increases. While serum AMH (sAMH) levels have been intensively investigated, there is less data regarding AMH concentrations in follicular fluid (FF), since FF has usually been designated as waste product during oocyte collection in assisted reproductive technologies. This pilot study investigated follicle AMH concentrations (fAMH) of several follicles per ovary, individually collected with the Steiner-Tan needle, and compared them to sAMH concentrations in women undergoing IVF treatment. We hypothesized that there is no difference of fAMH concentrations in individual follicles and that these concentrations resemble the sAMH value of the patient. METHODS: Patients were stimulated with a gonadotropin-releasing hormone antagonist ovarian hyperstimulation protocol. On the day of oocyte retrieval, serum samples and FF from all individual follicles from one stimulated IVF cycle were collected and individually analyzed for AMH concentrations. RESULTS: Intracyclic mean fAMH values (n follicle = 2-14) were significantly correlated to sAHM values (ρ = 0.85, p < 0.001) and showed a trend to be negatively associated with age (ρ = -0.43, p = 0.06). Mean intrapatient fAMH concentrations differed significantly (p < 0.001). Furthermore, significant correlations of sAMH with individual fAMH values of the first five follicles of each patient were observed. CONCLUSIONS: In conclusion, our results clearly showed that individual fAMH concentrations reflected sAMH values and that fAMH concentrations did not significantly differ within one patient. In future studies, it will be interesting to correlate individual fAMH values to the respective embryo development and overall pregnancy outcome in order to improve IVF treatments and to refrain from embryo overproduction.

Influence of acute normobaric hypoxia on physiological variables and lactate turn point determination in trained men.

The goal of this study is to evaluate the response of physiological variables to acute normobaric hypoxia compared to normoxia and its influence on the lactate turn point determination according to the three-phase model of energy supply (Phase I: metabolically balanced at muscular level; Phase II: metabolically balanced at systemic level; Phase III: not metabolically balanced) during maximal incremental exercise. Ten physically active (VO2max 3.9 [0.49] l·min(-1)), healthy men (mean age [SD]: 25.3 [4.6] yrs.), participated in the study. All participants performed two maximal cycle ergometric exercise tests under normoxic as well as hypoxic conditions (FiO2 = 14%). Blood lactate concentration, heart rate, gas exchange data, and power output at maximum and the first and the second lactate turn point (LTP1, LTP2), the heart rate turn point (HRTP) and the first and the second ventilatory turn point (VETP1, VETP2) were determined. Since in normobaric hypoxia absolute power output (P) was reduced at all reference points (max: 314 / 274 W; LTP2: 218 / 184 W; LTP1: 110 / 96 W), as well as VO2max (max: 3.90 / 3.23 l·min(-1); LTP2: 2.90 / 2.43 l·min(-1); LTP1: 1.66 / 1.52 l·min(-1)), percentages of Pmax at LTP1, LTP2, HRTP and VETP1, VETP2 were almost identical for hypoxic as well as normoxic conditions. Heart rate was significantly reduced at Pmax in hypoxia (max: 190 / 185 bpm), but no significant differences were found at submaximal control points. Blood lactate concentration was not different at maximum, and all reference points in both conditions. Respiratory exchange ratio (RER) (max: 1.28 / 1.08; LTP2: 1.13 / 0.98) and ventilatory equivalents for O2 (max: 43.4 / 34.0; LTP2: 32.1 / 25.4) and CO2 (max: 34.1 / 31.6; LTP2: 29.1 / 26.1) were significantly higher at some reference points in hypoxia. Significant correlations were found between LTP1 and VETP1 (r = 0.778; p < 0.01), LTP2 and HRTP (r = 0.828; p < 0.01) and VETP2 (r = 0.948; p < 0.01) for power output for both conditions. We conclude that the lactate turn point determination according to the three-phase-model of energy supply is valid in normobaric, normoxic as well as hypoxic conditions. The turn points for La, HR, and VE were reproducible among both conditions, but shifted left to lower workloads. The lactate turn point determination may therefore be used for the prescription of exercise performance in both environments. Key PointsThe lactate turn point concept can be used for performance testing in normoxic and hypoxic conditionsThe better the performance of the athletes the higher is the effect of hypoxiaThe HRTP and LTP2 are strongly correlated that allows a simple performance testing using heart rate measures only.

High-intensity interval training in patients with glaucoma (HIT-GLAUCOMA): protocol for a multicenter randomized controlled exercise trial.

Background: Glaucoma stands as a prominent global cause of irreversible blindness and the primary treatment approach involves reducing intraocular pressure (IOP). However, around one-third of patients exhibit disease progression despite effective IOP reduction. Microvascular endothelial function, chronic inflammation, and oxidative stress are known to affect retinal neuronal networks and have been associated with disease severity and progression. Exercise training has the potential to counteract these mechanisms as add-on treatment to usual care. Aims: The HIT-GLAUCOMA study will investigate the effects of a 6-month high-intensity interval training (HIIT) on intermediate endpoints such as local retinal microvascular and systemic large artery function, inflammation, and oxidative stress as well as clinical endpoints such as visual field indices, optic nerve rim assessment, retinal nerve fiber layer thickness, IOP, number of eye drops, vision-related quality of life and ocular surface disease symptomatology. Methods: The study is a multi-center randomized controlled clinical trial in patients with both normal tension and high-tension primary open angle glaucoma. Across two study centers, 128 patients will be enrolled and randomized on a 1:1 basis into an exercise intervention group and a usual care control group. The primary microvascular endpoints are retinal arteriolar and venular flicker light-induced dilation at 6 months. The primary endpoint in the systemic circulation is brachial artery flow-mediated dilation at 6 months. Anticipated results: We hypothesize that exercise therapy will improve retinal microvascular function and thus ocular blood flow in patients with glaucoma. As clinical outcomes, we will investigate the effect of exercise on visual field indices, optic nerve rim assessment, retinal nerve fiber layer thickness, IOP, number of eye drops, vision-related quality of life and ocular surface disease symptomatology. Discussion: HIT-GLAUCOMA is a blueprint trial design to study the effect of exercise training on neurodegenerative and cardiovascular diseases. Importantly, patients are also expected to benefit from improvements in general health and cardiovascular co-morbidities. If proven effective, exercise may offer a new add-on treatment strategy to slow glaucoma progression. Clinical Trial Registration Number: The trial is registered at Clinicaltrials.gov under the identifier NCT06058598 and is currently in the recruitment stage.

Human mesenchymal progenitor cells derived from alveolar bone and human bone marrow stromal cells: a comparative study.

The aim of the present study was to evaluate the potential of intraoral harvested alveolar bone as an alternative source of multipotent mesenchymal stromal cells for future applications in oral and maxillofacial tissue engineering. Explant cultures were established from 20 alveolar bone samples harvested from the oblique line immediately before wisdom tooth removal. Morphology and proliferation characteristics of the in vitro expanded cells, referred to as human alveolar bone-derived cells (hABDCs), were studied using phase-contrast microscopy. Immunocytochemical analysis of their surface marker expression was conducted using monoclonal antibodies defining mesenchymal stromal cells. To evaluate their multilineage differentiation potential, hABDCs were induced to differentiate along the osteogenic, adipogenic, and chondrogenic lineage and compared to bone marrow mesenchymal stromal cells (hBMSCs) on mRNA and protein levels applying RT-PCR and cytochemical staining methods. hABDCs showed typical morphological characteristics comparable to those of hBMSCs such as being mononuclear, fibroblast-like, spindle-shaped, and plastic adherent. Immunophenotypically, cells were positive for CD105, CD90, and CD73 while negative for CD45, CD34, CD14, CD79α, and HLA-DR surface molecules, indicating an antigen expression pattern considered typical for multipotent mesenchymal stromal cells. As evidenced by RT-PCR and cytochemistry, hABDCs showed multilineage differentiation and similar chondrogenic and osteogenic differentiation potentials when compared to hBMSCs. Our findings demonstrate that human alveolar bone contains mesenchymal progenitor cells that can be isolated and expanded in vitro and are capable of trilineage differentiation, providing a reservoir of multipotent mesenchymal cells from an easily accessible tissue source.

Body composition in sport: a comparison of a novel ultrasound imaging technique to measure subcutaneous fat tissue compared with skinfold measurement.

BACKGROUND: Extremely low weight and rapid changes in weight and body composition have become major concerns in many sports, but sufficiently accurate field methods for body composition assessment in athletes are missing. This study aimed to explore the use of ultrasound methods for assessment of body fat content in athletes. METHODS: 19 female athletes (stature: 1.67(± 0.06) m, weight: 59.6(± 7.6) kg; age: 19.5(± 3.3) years) were investigated by three observers using a novel ultrasound method for thickness measurement of uncompressed subcutaneous adipose tissue and of embedded structures. Two observers also measured skinfold thickness at eight International Society for the Advancement of Kinanthrometry (ISAK) sites; mean skinfold values were compared to mean subcutaneous adipose tissue thicknesses measured by ultrasound. Interobserver reliability of imaging and evaluation obtained by this ultrasound technique: intraclass correlation coefficient ICC=0.968 (95% CI 0.957 to 0.977); evaluation of given images: ICC=0.997 (0.993 to 0.999). RESULTS: Skinfold compared to ultrasound thickness showed that compressibility of subcutaneous adipose tissue depends largely on the site and the person: regression slopes ranged from 0.61 (biceps) to 1.59 (thigh) and CIs were large. Limits of agreement ranged from 2.6 to 8.6 mm. Regression lines did not intercept the skinfold axis at zero because of the skin thickness being included in the skinfold. The four ISAK trunk sites caused ultrasound imaging problems in 13 of 152 sites (8 ISAK sites, 19 athletes). CONCLUSIONS: The ultrasound method allows measurement of uncompressed subcutaneous adipose tissue thickness with an accuracy of 0.1-0.5 mm, depending on the probe frequency. Compressibility of the skinfold depends on the anatomical site, and skin thickness varies by a factor of two. This inevitably limits the skinfold methods for body fat estimation. Ultrasound accuracy for subcutaneous adipose tissue measurement is limited by the plasticity of fat and furrowed tissue borders. Comparative US measurements show that skinfold measurements do not allow accurate assessment of subcutaneous adipose tissue thickness.

Body composition in sport: interobserver reliability of a novel ultrasound measure of subcutaneous fat tissue.

BACKGROUND: Very low body mass, extreme mass changes, and extremely low per cent body fat are becoming increasingly common in many sports, but sufficiently reliable and accurate field methods for body composition assessment in athletes are missing. METHODS: Nineteen female athletes were investigated (mean (SD) age: 19.5 (± 3.3) years; body mass: 59.6 (± 7.6) kg; height: 1.674 (± 0.056) m; BMI: 21.3 (± 2.3) kg/m(2)). Three observers applied diagnostic B-mode-ultrasound (US) combined with the evaluation software for subcutaneous adipose tissue measurements at eight ISAK sites (International Society for the Advancement of Kinanthrometry). Regression and reliability analyses are presented. RESULTS: US measurements and evaluation of subcutaneous adipose tissue (SAT) thicknesses (including fibrous structures: D(included); n=378) resulted in an SE of estimate SEE=0.60 mm, R(2)=0.98 (p<0.001), limit of agreement LOA=1.18, ICC=0.968 (0.957-0.977). Similar values were found for D(excluded): SEE=0.68 mm, R(2)=0.97 (p<0.001). D(included) at individual ISAK sites: at biceps, R(2)=0.87 and intraclass-correlation coefficient ICC=0.811 were lowest and SEE=0.79 mm was highest. Values at all other sites ranged from R(2): 0.94-0.99, SEE: 0.42-0.65 mm, and ICC: 0.917-0.985. Interobserver coefficients ranged from 0.92 to 0.99, except for biceps (0.74, 0.83 and 0.87). Evaluations of 20 randomly selected US images by three observers (D(included)) resulted in: SEE=0.15 mm, R(2)=0.998(p<0.001), ICC=0.997 (0.993, 0999). CONCLUSIONS: Subject to optimal choice of sites and certain standardisations, US can offer a highly reliable field method for measurement of uncompressed thickness of the SAT. High accuracy and high reliability of measurement, as obtained with this US approach, are essential for protection of the athlete's health and also for optimising performance.

Untargeted sequencing of circulating microRNAs in a healthy and diseased older population.

We performed untargeted profiling of circulating microRNAs (miRNAs) in a well characterized cohort of older adults to verify associations of health and disease-related biomarkers with systemic miRNA expression. Differential expression analysis revealed 30 miRNAs that significantly differed between healthy active, healthy sedentary and sedentary cardiovascular risk patients. Increased expression of miRNAs miR-193b-5p, miR-122-5p, miR-885-3p, miR-193a-5p, miR-34a-5p, miR-505-3p, miR-194-5p, miR-27b-3p, miR-885-5p, miR-23b-5b, miR-365a-3p, miR-365b-3p, miR-22-5p was associated with a higher metabolic risk profile, unfavourable macro- and microvascular health, lower physical activity (PA) as well as cardiorespiratory fitness (CRF) levels. Increased expression of miR-342-3p, miR-1-3p, miR-92b-5p, miR-454-3p, miR-190a-5p and miR-375-3p was associated with a lower metabolic risk profile, favourable macro- and microvascular health as well as higher PA and CRF. Of note, the first two principal components explained as much as 20% and 11% of the data variance. miRNAs and their potential target genes appear to mediate disease- and health-related physiological and pathophysiological adaptations that need to be validated and supported by further downstream analysis in future studies.Clinical Trial Registration: ClinicalTrials.gov: NCT02796976 ( https://clinicaltrials.gov/ct2/show/NCT02796976 ).

Corrigendum: Acute Exercise-Induced Oxidative Stress Does Not Affect Immediate or Delayed Precursor Cell Mobilization in Healthy Young Males.

[This corrects the article DOI: 10.3389/fphys.2020.577540.].

MiRNA126 - RGS16 - CXCL12 Cascade as a Potential Mechanism of Acute Exercise-Induced Precursor Cell Mobilization.

Acute exercise enhances circulating stem and precursor cells (CPCs) in the peripheral blood. The responsible mechanisms and molecular pathways, however, have not been fully identified. The aim of the present study was to investigate a pathway related to elevated levels of apoptotic peripheral blood mononuclear cells (MNCs) and their secretome. An increased uptake of miRNA126 in MNCs was suggested to lead to reduced levels of RGS16 mRNA and, in turn, an enhanced translation and secretion of CXCL12. Eighteen healthy, young men underwent two identical incremental cycling exercises of which the first served as control while the second was preceded by a 7-day-long antioxidative supplementation. Blood samples were collected at baseline (-10min) and several time points after exercise (0, 30, 90, 180, and 270min). Relative concentrations of miRNA126 in MNCs and CXCL12 levels in plasma were determined at all time points while RGS16 mRNA was assessed in MNCs at baseline and 30min after exercise. CXCL12 increased after exercise and strongly correlated with CPC numbers. MiRNA126 increased 30min and, to a lesser extent, also 180 and 270min after exercise but only with supplementation. RGS16 mRNA decreased 30min after exercise independent of the intervention. The amount of RGS16 mRNA inversely correlated with levels of miRNA126, but not with plasma CXCL12. In conclusion, even though plasma CXCL12 correlated with CPC numbers, the increase in CXCL12 cannot be explained by the increased concentration of miRNA126 and lower RGS16 mRNA in MNCs that would have allowed for an enhanced translation of CXCL12. Clinical Trial Registration: ClinicalTrials.gov, NCT03747913. Registered 20 November 2018, https://clinicaltrials.gov/ct2/show/NCT03747913.

Acute exercise-induced glycocalyx shedding does not differ between exercise modalities, but is associated with total antioxidative capacity.

OBJECTIVES: Regular physical exercise is known to protect endothelial integrity. It has been proposed that acute exercise-induced changes of the (anti-)oxidative system influence early (glycocalyx shedding) and sustained endothelial activation (shedding of endothelial cells, ECs) as well as endothelial-cell repair by circulating hematopoietic stem and progenitor cells (HPCs). However, results are not conclusive and data in trained participants performing different exercise modalities is lacking. DESIGN: Eighteen healthy, well-trained participants (9 runners, 9 cyclists; age: 29.7 ±â€¯4.2 yrs) performed a strenuous acute exercise session consisting of 4 bouts of 4-min high-intensity with decreasing power profile and 3-min low-intensity in-between. METHODS: Average power/speed of intense phases was 85% of the peak achieved in a previous incremental test. Before and shortly after exercise, total oxidative and antioxidative capacities (TAC), shedding of syndecan-1, heparan sulfate, hyaluronan, ECs, and circulating HPCs were investigated. RESULTS: TAC decreased from 1.81 ±â€¯0.42 nmol/L to 1.47 ±â€¯0.23 nmol/L post-exercise (p = 0.010) only in runners. Exercise-induced early and sustained endothelial activation were enhanced post-exercise- syndecan-1: 103.2 ±â€¯63.3 ng/mL to 111.3 ±â€¯71.3 ng/mL, heparan sulfate: from 2637.9 ±â€¯800.1 ng/mL to 3197.1 ±â€¯1416.3 ng/mL, both p < 0.05; hyaluronan: 84.3 ±â€¯21.8 ng/mL to 121.4 ±â€¯29.4 ng/mL, ECs: from 6.6 ±â€¯4.5 cells/µL to 9.5 ±â€¯6.2 cells/µL, both p < 0.01; results were not different between exercise modalities and negatively related to TAC concentrations post-exercise. HPC proportions and self-renewal ability were negatively, while EC concentrations were positively associated with circulating hyaluronan concentrations. CONCLUSIONS: These results highlight the importance of the antioxidative system to prevent the endothelium from acute exercise-induced vascular injury - independent of exercise modality - in well-trained participants. Endothelial-cell repair is associated with hyluronan signaling, possibly a similar mechanism as in wound repair.

High-Intensity Interval Training for Heart Failure Patients With Preserved Ejection Fraction (HIT-HF)-Rational and Design of a Prospective, Randomized, Controlled Trial.

Background: The pathophysiology of HF with preserved ejection fraction (HFpEF) has not yet been fully understood and HFpEF is often misdiagnosed. Remodeling and fibrosis stimulated by inflammation appear to be main factors for the progression of HFpEF. In contrast to patients with HF with reduced ejection fraction, medical treatment in HFpEF is limited to relieving HF symptoms. Since mortality in HFpEF patients remains unacceptably high with a 5-year survival rate of only 30%, new treatment strategies are urgently needed. Exercise seems to be a valid option. However, the optimal training regime still has to be elucidated. Therefore, the aim of the study is to investigate the effects of a high-intensity interval (HIT) training vs. a moderate continuous training (MCT) on exercise capacity and disease-specific mechanisms in a cohort of patients with HFpEF. Methods: The proposed study will be a prospective, randomized controlled trial in a primary care setting including 86 patients with stable HFpEF. Patients will undergo measurements of exercise capacity, disease-specific blood biomarkers, cardiac and arterial vessel structure and function, total hemoglobin mass, metabolic requirements, habitual physical activity, and quality of life (QoL) at baseline and follow-up. After the baseline visit, patients will be randomized to the intervention or control group. The intervention group (n = 43) will attend a supervised 12-week HIT on a bicycle ergometer combined with strength training. The control group (n = 43) will receive an isocaloric supervised MCT combined with strength training. After 12 weeks, study measurements will be repeated in all patients to quantify the effects of the intervention. In addition, telephone interviews will be performed at 6 months, 1, 2, and 3 years after the last visit to assess clinical outcomes and QoL. Discussion: We anticipate clinically significant changes in exercise capacity, expressed as VO2peak, as well as in disease-specific mechanisms following HIT compared to MCT. Moreover, the study is expected to add important knowledge on the pathophysiology of HFpEF and the clinical benefits of a training intervention as a novel treatment strategy in HFpEF patients, which may help to improve both QoL and functional status in affected patients. Trial registration: ClinicalTrials.gov, identifier: NCT03184311, Registered 9 June 2017.

Acute Exercise-Induced Oxidative Stress Does Not Affect Immediate or Delayed Precursor Cell Mobilization in Healthy Young Males.

Exercise is known to acutely and transiently mobilize precursor cells to the peripheral blood. To date, the underlying mechanisms have not yet been fully elucidated and we hypothesized that exercise-induced oxidative stress could be a mobilizing agent, either directly or via circulating apoptotic cells as mediators. The aim of the study was to assess the effect of acute exercise-induced oxidative stress on numbers of circulating angiogenic precursor cells (CACs), circulating non-angiogenic precursor cells (nCACs), mesenchymal precursor cells (MPCs), mature endothelial cells (ECs), and mononuclear cells (MNCs), as well as their apoptotic subsets. Healthy, young males (n = 18, age: 24.2 ± 3.5 years) completed two identical, standardized incremental cycling tests. The first, un-supplemented control test was followed by a 7-day-long supplementation of vitamin C (1,000 mg/day) and E (400 I.U./day), immediately preceding the second test. Blood samples were collected before, directly after, 30, 90, 180, and 270 min after exercise, and aforementioned circulating cell numbers were determined by flow cytometry and a hematology analyzer. Additionally, total oxidative capacity (TOC) and total antioxidative capacity (TAC) were measured in serum at all timepoints. Antioxidative supplementation abolished the exercise-induced increase in the oxidative stress index (TOC/TAC), and reduced baseline concentrations of TOC and TOC/TAC. However, it did not have any effect on CACs, nCACs, and MPC numbers or the increase in apoptotic MNCs following exercise. Our results indicate that exercise-induced oxidative stress is neither a main driver of lymphocyte and monocyte apoptosis, nor one of the mechanisms involved in the immediate or delayed mobilization of precursor cells.

Exercise-Induced Circulating Hematopoietic Stem and Progenitor Cells in Well-Trained Subjects.

It has been proposed that exercise-induced systemic oxidative stress increases circulating hematopoietic stem and progenitor cell (HPC) number in active participants, while HPC clonogenicity is reduced post-exercise. However, HPCs could be protected against exercise-induced reactive oxygen species in a trained state. Therefore, we characterized the acute exercise-induced HPC profile of well-trained participants including cell number, clonogenicity, and clearance. Twenty-one healthy, well-trained participants-12 runners, 9 cyclists; age 30.0 (4.3) years-performed a strenuous acute exercise session consisting of 4 bouts of 4-min high-intensity with 3-min low-intensity in-between, which is known to elicit oxidative stress. Average power/speed of intense phases was 85% of the peak achieved in a previous incremental test. Before and 10 min after exercise, CD34+/45dim cell number and clonogenicity, total oxidative (TOC), and antioxidative (TAC) capacities, as well as CD31 expression on detected HPCs were investigated. TOC significantly decreased from 0.093 (0.059) nmol/l to 0.083 (0.052) nmol/l post-exercise (p = 0.044). Although HPC proportions significantly declined below baseline (from 0.103 (0.037)% to 0.079 (0.028)% of mononuclear cells, p < 0.001), HPC concentrations increased post-exercise [2.10 (0.75) cells/µl to 2.46 (0.98) cells/µl, p = 0.002] without interaction between exercise modalities, while HPC clonogenicity was unaffected. Relating HPC concentrations and clonogenicity to exercise session specific (anti-) oxidative parameters, no association was found. CD31 median fluorescent intensity expression on detected HPCs was diminished post-exercise [from 1,675.9 (661.0) to 1,527.1 (558.9), p = 0.023] and positively correlated with TOC (r rm = 0.60, p = 0.005). These results suggest that acute exercise-reduced oxidative stress influences HPC clearance but not mobilization in well-trained participants. Furthermore, a well-trained state protected HPCs' clonogenicity from post-exercise decline.

Endometriosis accelerates synchronization of early embryo cell divisions but does not change morphokinetic dynamics in endometriosis patients.

OBJECTIVE: The pathology of endometriosis and its impact on embryo development is still a black box in reproductive medicine. In this time-lapse study we investigated the influence of endometriosis on morphokinetic parameters of embryo development, taking variables of dynamic monitoring into account. Furthermore we evaluated reproductive medicine treatment outcome such as fetal heartbeat and live birth rate. METHODS: 1148 embryos (control: n = 596, endometriosis: n = 552) were retrospectively analyzed. Patients were stimulated with GnRH antagonist protocol. After fertilization, embryos were incubated in a time-lapse system (EmbryoScope). RESULTS: The mixed-model analysis revealed a significant main effect of time (p<0.001), with post-hoc tests showing that any time needed to reach a specific developmental stage was significantly different from all the others (all p<0.001). Embryos of endometriosis patients showed the same absolute morphokinetic time parameters as the control group, however, synchronization of early embryo cell divisions (s2) was faster in endometriosis patients compared to the control group. CONCLUSION: In general, endometriosis does not induce changes in early embryo morphokinetics. However, observed acceleration in cell cycle synchronization of embryo cleavage patterns might be a missing explanation for contradicting results in literature regarding the impairments in reproductive medicine treatment outcome of endometriosis patients.