Acute exercise activates the AHR in peripheral blood mononuclear cells in an intensity-dependent manner.

The kynurenine pathway of tryptophan degradation generates several metabolites such as kynurenine or kynurenic acid that serve as endogenous ligands of the aryl hydrocarbon receptor (AHR). Due to its distinct biological roles particularly modulating the immune system, the AHR is a current therapeutic target across different inflammation-related diseases. Here, we show an acute exercise-induced increase in AHR ligand availability on a systemic level and a kynurenine pathway activation in peripheral blood mononuclear cells (PBMCs). Concurrently, the AHR is activated in PBMCs following acute exercise. Exercise effects on both, kynurenic acid and AHR activation in PBMCs were greater in response to high-intensity interval exercise (50 min., six three-minute intervals á 90% V̇O2peak, and three-minute intervals at 50% V̇O2peak in between) compared to workload-matched moderate intensity continuous exercise (50 min.). In conclusion, these data indicate a novel mechanistic link how exercise modulates the immune system through the kynurenine pathway-AHR axis, potentially underlying exercise-induced benefits in various chronic diseases.

Kinetics of immune cell mobilization during acute aerobic exercise in healthy adults.

While pre-post differences in immune cell mobilization after acute aerobic exercise are well investigated, less is known about when and to what extent immune cells are mobilized during acute aerobic exercise. This experimental trial aimed to investigate the detailed kinetics of circulating immune cells in twelve healthy adults (n=6 females) who completed a 40-min aerobic exercise bout at 60% of the participants' V̇O2peak on a bicycle ergometer. Cellular inflammation markers and sex-dependent differences in circulating immune cells were analyzed. Blood samples were taken immediately before, after warm-up, during exercise after 5 min, 10 min, 15 min, 30 min, 40 min (cessation), and 60 min post exercise. Significant increases in leukocytes (p<0.001), lymphocytes (p<0.001), neutrophils (p=0.003) and platelets (p=0.047) can be observed after five min of exercise. The cellular inflammation markers show significant alterations only post exercise. Significant sex differences were observed for neutrophils (p=0.049) and neutrophil-to-lymphocyte ratio (p=0.007) one hour post exercise. These results indicate that i) leukocytes are already mobilized after 5 min of moderate-to-vigorous aerobic exercise, ii) the magnitude of exercise induced leukocyte mobilization is dependent on exercise duration, iii) integrative cellular inflammation markers are only altered after exercise cessation, and iv) the observed effects might be sex-dependent.

Cycling in primary progressive multiple sclerosis (CYPRO): study protocol for a randomized controlled superiority trial evaluating the effects of high-intensity interval training in persons with primary progressive multiple sclerosis.

BACKGROUND: Primary progressive multiple sclerosis (PPMS) is the least prevalent multiple sclerosis (MS) phenotype. For persons with PPMS (pwPPMS), pharmacological treatment options are limited. As a complementary non-pharmacological treatment, endurance training improves the health-related quality of life (HRQoL), numerous MS symptoms, and MS-related performance impediments. High-intensity interval training (HIIT) has been shown to induce superior effects compared to moderate-intensity continuous training (MCT). As current evidence is based on MS samples with mixed phenotypes, generalizability to pwPPMS remains unclear. METHODS: CYPRO is a parallel-group, single-center, and single-blind randomized controlled superiority trial evaluating the effects of HIIT compared to MCT in pwPPMS. Sixty-one pwPPMS are randomized (1:1) to perform volume-matched HIIT or MCT sessions on bicycle ergometers two to three times per week in addition to standard rehabilitative care during their three-week inpatient stay at Valens rehabilitation clinic, Switzerland. Standard rehabilitative care comprises endurance and strength training, physiotherapy, and occupational therapy. HIIT sessions include six 90-second intervals at 95% peak heart rate (HRpeak), interspersed by 90-second active breaks with unloaded pedaling, aimed to reach 60%HRpeak. MCT represents the standard treatment at Valens rehabilitation clinic and is performed as continuous cycling at 60%HRpeak for the duration of 26 minutes. The primary outcome is cardiorespiratory fitness, assessed as peak oxygen consumption (V̇O2peak) during cardiopulmonary exercise testing (CPET). Secondary outcomes include peak power output during CPET, walking capacity, cognitive performance, HRQoL, fatigue, anxiety and depressive symptoms, and blood-derived biomarkers (e.g., serum neurofilament light chain, glial fibrillary acidic protein, kynurenine pathway metabolites) related to MS pathophysiology. All outcomes are assessed at baseline and discharge after three weeks. Venous blood sampling is additionally performed immediately and two hours after the first HIIT or MCT session. DISCUSSION: CYPRO will expand current knowledge on symptom management and rehabilitation in MS to the subpopulation of pwPPMS, and will contribute to the exploration of potential disease-modifying effects of endurance training in MS. The superiority design of CYPRO will allow deriving explicit recommendations on endurance training design in pwPPMS that can be readily translated into clinical practice. TRIAL REGISTRATION: CYPRO has been prospectively registered at ClinicalTrials.gov on 8 February 2022 (NCT05229861).

12-week combined strength and endurance exercise attenuates CD8+ T-cell differentiation and affects the kynurenine pathway in the elderly: a randomized controlled trial.

BACKGROUND: Age-related accumulation of highly differentiated CD8+ effector memory re-expressing CD45RA (EMRA) T-cells and disruption of the kynurenine (KYN) pathway are associated with chronic inflammation and the development of insulin resistance. In this study the aim was to investigate the effects of 12-week combined strength and endurance exercise on CD8+ T-cell differentiation and KYN pathway metabolites. Ninety-six elderly subjects (f/m, aged 50-70) were randomized to a control (CON) or exercise (EX) group. The EX group completed combined strength and endurance training twice weekly for one hour each time at an intensity of 60% of the one-repetition maximum for strength exercises and a perceived exertion of 15/20 for endurance exercises. The EX group was also randomly subdivided into two groups with or without a concomitant balanced diet intervention in order to examine additional effects besides exercise alone. Before and after the intervention phase, the proportions of CD8+ T-cell subsets and levels of KYN pathway metabolites in peripheral blood were determined. RESULTS: The CD8+ EMRA T-cell subsets increased in the CON group but remained almost unchanged in the EX group (p = .02). Plasma levels of kynurenic acid (KA) increased in the EX group and decreased in the CON group (p = .03). Concomitant nutritional intervention resulted in lower levels of quinolinic acid (QA) compared with exercise alone (p = .03). Overall, there was a slight increase in the QA/KA ratio in the CON group, whereas it decreased in the EX group (p > .05). CONCLUSIONS: Combined strength and endurance training seems to be a suitable approach to attenuate CD8+ T-cell differentiation in the elderly and to redirect the KYN pathway towards KA. The clinical relevance of these effects needs further investigation.

Cellular Integrative Immune Markers in Elite Athletes.

The integrative immune markers neutrophil-lymphocyte-ratio (NLR), platelet-lymphocyte-ratio (PLR) and systemic immune inflammation index (SII) are established markers in clinical patient care. Adoption of these markers in elite athletics might prove beneficial for monitoring training and health. Blood samples of 195 healthy national Olympic squad athletes were collected before a graded bicycle-ergometric exercise test until complete exhaustion. Measurements included white blood cells, lymphocytes and platelets, allowing for the calculation of the integrative immune markers. Correlations between athlete characteristics (sex, age, sporting discipline, training experience, training volume) and integrative immune marker-values were assessed. In a subgroup analysis a second blood sample was collected from 25 athletes at 1 minute after exercise test to assess its effect on the immune marker levels.An inverse correlation between peak power output and SII-level (Pearson correlation coefficient=-.270, p<.001) and NLR-level (Pearson correlation coefficient=-.249, p<.001) was found. Athletes with higher aerobic fitness had significantly lower values of SII and PLR compared to athletes with lower aerobic fitness. An elevated SII (p=.003) and a reduced PLR (p=.001) was documented as acute response to the exercise test. The integrative immune markers might be a promising tool for monitoring training and health in elite athletes.

Distinct distribution patterns of exercise-induced natural killer cell mobilization into the circulation and tumor tissue of patients with prostate cancer.

The mobilization and activation of natural killer (NK) cells have been proposed as key mechanisms promoting anti-oncogenic effects of physical exercise. Although mouse models have proven that physical exercise recruits NK cells to tumor tissue and inhibits tumor growth, this preclinical finding has not been transferred to the clinical setting yet. In this first-in-human study, we found that physical exercise mobilizes and redistributes NK cells, especially those with a cytotoxic phenotype, in line with preclinical models. However, physical exercise did not increase NK cell tumor infiltrates. Future studies should carefully distinguish between acute and chronic exercise modalities and should be encouraged to investigate more immune-responsive tumor entities.

Exercise reduces systemic immune inflammation index (SII) in childhood cancer patients.

While exercise and physical activity have been suggested to reduce mortality and symptoms in cancer, knowledge on these associations in patients with childhood cancer (CCPs) is sparse. Anti-inflammatory properties of exercise might mediate these beneficial effects. We investigated the influence of exercise on the inflammation markers neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and systemic-immune-inflammation index (SII) and associations to patient-reported-outcomes in CCPs in a randomized-controlled trial. Results show associations between inflammation markers and patient-reported outcomes. Compared to the control group, SII was significantly reduced following exercise (p=0.036). Anti-inflammatory effects of exercise are also present in CCPs and may underlie exercise-induced benefits on symptoms. Clinical Trial Registration Number: NCT02612025.

Sleep problems and their interaction with physical activity and fatigue in hematological cancer patients during onset of high dose chemotherapy.

PURPOSE: Sleep problems reported by hematological cancer patients are usually linked to higher levels of cancer-related fatigue. Although the awareness of sleep problems in solid cancer patients is rising, there has been less attention to the issue in hematological cancer patients. The present study assesses the differences in sleep by comparing physical activity and fatigue levels among hematological cancer patients during the onset of chemotherapy. Furthermore, it investigates the relationship between sleep, physical activity, and fatigue through mediation analysis. METHODS: The recruited sample consists of 58 newly diagnosed hematological cancer patients (47.1 ± 15.4 yrs; 51.7% males). Subjects completed questionnaires assessing sleep (PSQI), physical activity (visual analogue scale), fatigue (MFI-20), anxiety, depression (HADS), and quality of life (EORTC QLQ-C30) within two weeks from starting treatment. RESULTS: The sample reported more sleep problems in comparison to the German population norm. The classification as good (ca 25%) or bad sleepers (ca 75%) showed less frequent physical activity (p = .04), higher fatigue (p = .032), anxiety (p = .003), depression (p = .011) and pain (p = .011) in bad sleepers. The mediation analysis revealed significant indirect effects of sleep on fatigue through physical activity habits. CONCLUSIONS: This study highlights the combined action of sleep problems and physical activity on fatigue during the onset of induction chemotherapy. These two parameters could represent meaningful intervention targets to improve a patient's status during chemotherapy. TRIAL REGISTRATION: The study was registered on the WHO trial register (DRKS00007824).

High-intensity interval training reduces neutrophil-to-lymphocyte ratio in persons with multiple sclerosis during inpatient rehabilitation.

In persons with multiple sclerosis (PwMS), the neutrophil-to-lymphocyte ratio (NLR) is associated with disability status, symptomatology and disease activity. High-intensity interval training (HIIT) improves many symptoms in PwMS and may positively influence disease progression. Here, we present results from a randomized controlled trial during inpatient rehabilitation on immediate (single bout) and training (3-week intervention) effects of HIIT versus moderate continuous training on NLR and related cellular inflammation markers. Only HIIT reduced the NLR over the 3-week intervention period. These training effects might be due to repetitive inflammatory states with compensatory anti-inflammatory counterbalancing after each HIIT session.

The effect of exercise on regulatory T cells: A systematic review of human and animal studies with future perspectives and methodological recommendations.

Many of the exercise-related health-promoting effects are attributed to beneficial immunomodulation. The restoration of immune homeostasis is context-dependent, meaning either to increase anti-inflammatory signaling to counteract disease progression of non-communicable (auto)inflammatory diseases or to enhance (local) activity of proinflammatory immune cells to slow down or inhibit cancer progression. Regulatory CD4+ T cells (Tregs) represent the main regulatory component of the adaptive immune system that fine-tunes inflammatory responses, keeps them in check and prevents long-lasting autoimmunity. Because often dysregulated in the context of various diseases, emerging treatment approaches aim to modulate their number or inherent anti-inflammatory and immunosuppressive function in a highly disease-specific way. Exercise represents a non-pharmacologic strategy in disease prevention and rehabilitation and may be an effective treatment with few to no side effects to counteract dysregulation of Tregs. To date, several studies have evaluated the effect of exercise on Treg-related outcomes. This review aims at providing a comprehensive overview on alterations of blood- or tissue-derived Treg counts, proportion and functionality following acute and chronic exercise in humans and animal models. From the 60 reviewed studies, an overall disease-specific beneficial effect of chronic exercise on Treg levels in animal models can be stated, while both acute and chronic effects in human studies are less definite. However, Treg phenotyping is less sufficient in the animal studies compared to human studies. Only a limited number of studies investigated Treg functionality. There is a large heterogeneity concerning study design, human population or animal model, exercise protocol, and Treg outcome measure specification which makes it difficult to compare results and draw clear conclusions. Study results are discussed in the context of current concepts in exercise immunology. Finally, future perspectives and methodological recommendations are provided to promote research in this field.

High-intensity interval training and energy management education, compared with moderate continuous training and progressive muscle relaxation, for improving health-related quality of life in persons with multiple sclerosis: study protocol of a randomized controlled superiority trial with six months' follow-up.

BACKGROUND: Persons with multiple sclerosis (PwMS) often have reduced aerobic capacity and report fatigue as the most disabling symptom impacting their health-related quality of life (HRQoL). A multidisciplinary rehabilitation approach is recommended for successful management of symptoms, although there is little supporting evidence. The aim of this study is to evaluate the effect of a multimodal therapy approach, including endurance training and patient education, during a three-week inpatient rehabilitation stay, on HRQoL in PwMS at six months follow-up. Inpatient energy management education (IEME) + high-intensity interval training (HIIT) will be compared with progressive muscle relaxation (PMR) + moderate continuous training (MCT). METHODS: This study has a two-armed single-blind randomized controlled superiority trial design. One hundred six PwMS-related fatigue (relapsing-remitting or chronic progressive phenotypes; Expanded Disability Status Scale (EDSS) ≤ 6.5) will be recruited at the Valens clinic, Switzerland, and randomized into either an experimental (EG) or a control group (CG). EG: participants will perform IEME twice and HIIT three times per week during the three-week rehabilitation stay. IEME is a group-based intervention, lasting for 6.5 h over three weeks. HIIT contains of five 1.5-min high-intensive exercise bouts on a cycle ergometer at 95-100% of peak heart rate (HRpeak), followed by active breaks of unloaded pedalling for 2 min to achieve 60% of HRpeak. CG: participants will perform PMR twice and MCT three times per week during the three-week rehabilitation stay, representing local usual care. PMR consists of six 1-h relaxation group sessions. MCT consists of 24-min continuous cycling at 65% of HRpeak. The primary outcome is HRQoL (Physical and Mental Component Summaries of the Medical Outcome Study 36-item Short Form Health Survey; SF-36), measured at entry to the clinic (baseline, T0), three weeks after T0 (T1) and at four (T2) and six (T3) months after T0. Secondary outcomes comprise cardiorespiratory fitness, inflammatory markers (measured at T0 and T1), fatigue, mood, self-efficacy, occupational performance, physical activity (measured at T0, T1, T2 and T3) and behaviour changes in energy management (measured at T2 and T3). DISCUSSION: This study will provide detailed information on a multimodal therapy approach to further improve rehabilitation for PwMS. TRIAL REGISTRATION: This trial was prospectively registered at ClinicalTrials.gov ( NCT04356248 ; 22 April 2020).

Feasibility and suitability of a graded exercise test in patients with aggressive hemato-oncological disease.

PURPOSE: Physical activity promises to reduce disease-related symptoms and therapy-related side effects in patients suffering from aggressive lymphoma (L) or acute leukemia (AL). For an efficient training program, determination of patients' physical capacity with a purposive exercise test is crucial. Here, we evaluated the feasibility and suitability of a graded exercise test (GXT) frequently applied in patients suffering from solid tumors by assessing whether patients achieved criteria for maximal exercise testing according to the American College of Sports Medicine (ACSM). METHODS: The GXT was performed by 51 patients with an aggressive L or AL prior to the start or in the earliest possible phase of high-dose chemotherapy, following a recommended protocol for cancer patients, starting at 20 Watts (W), with an increase of 10 W/min until volitional exhaustion. Subsequently, we investigated whether the following ACSM criteria were fulfilled: (1) failure of heart rate to increase despite increasing workload, (2) post-exercise capillary lactate concentration ≥ 8.0 mmol L-1, (3) rating of perceived exertion at exercise cessation > 17 on the 6-20 Borg Scale. RESULTS: Out of 51 patients, two, six, and 35 participants met the first, second, and third criterion, respectively. No relevant relationships between the completion of the criteria and patients' characteristics (e.g., gender, age) were found. CONCLUSION: Although results of this study suggest a general feasibility of the applied GXT, the ACSM criteria were not met by the majority of the participants. Therefore, this study raises doubts about the suitability of the GXT protocol and the ACSM criteria for this group of patients.

Transferring clinically established immune inflammation markers into exercise physiology: focus on neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and systemic immune-inflammation index.

Over the last decades the cellular immune inflammation markers neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII = NLR × platelets) have emerged in clinical context as markers of disease-related inflammation and are now widely appreciated due to their integrative character. Transferring these clinically established inflammation markers into exercise physiology seems highly beneficial, especially due to the low temporal, financial and infrastructural resources needed for assessment and calculation. Therefore, the aim of this review is to summarize evidence on the value of the integrative inflammation markers NLR, PLR and SII for depiction of exercise-induced inflammation and highlight potential applications in exercise settings. Despite sparse evidence, multiple investigations revealed responsiveness of the markers to acute and chronic exercise, thereby opening promising avenues in the field of exercise physiology. In performance settings, they might help to infer information for exercise programming by reflecting exercise strain and recovery status or periods of overtraining and increased infection risk. In health settings, application involves the depiction of anti-inflammatory effects of chronic exercise in patients exhibiting chronic inflammation. Further research should, therefore, focus on establishing reference values for these integrative markers in athletes at rest, assess the kinetics and reliability in response to different exercise modalities and implement the markers into clinical exercise trials to depict anti-inflammatory effects of chronic exercise in different patient collectives.

Acute exercise impacts AhR and PD-1 levels of CD8+ T-cells-Exploratory results from a randomized cross-over trial comparing endurance versus resistance exercise.

PURPOSE: The programmed cell death protein 1 (PD-1) has become a promising target in cancer immunotherapy. PD-1 expression of CD8+ T-cells may be increased via the exploitation of aryl hydrocarbon receptor (AhR) signaling with kynurenine (KYN) as a ligand. Since exercise affects KYN metabolism, we exploratory investigated the influence of acute exercise bouts on AhR and PD-1 levels of CD8+ T-cells. METHOD: In this study, 24 healthy males (age: 24.6 ± 3.9 years; weight 83.9 ± 10.5 kg; height: 182.4 ± 6.2 cm) completed a single bout of endurance (EE) and resistance exercise (RE) in a randomly assigned order on separate days. Blood samples were drawn before (t0), after (t1), and 1 h after (t2) both conditions. T-cell populations, the level of cytoplasmic AhR, and surface PD-1 were assessed by flow cytometry. RESULTS: T-cell populations changed over time, indicated by an increase in the absolute numbers of CD3+ lymphocytes after EE (p < .001) and RE (p = .036) and in PD-1+ CD8+ T-cells after EE (p = .021). Proportions of T-cell populations changed only after EE (t0-t2: p = .029; t1-t2: p = .006). The level of cytoplasmic AhR decreased immediately after exercise in both exercise conditions (EE: p = .009; RE: p = .036). The level of surface PD-1 decreased 1 h after EE (p = .005). CONCLUSION: We analyzed the level of surface PD-1 and cytoplasmic AhR following acute physical exercise for the first time. Especially EE was observed to impact both AhR and PD-1 levels, undermining its role as the AhR-PD-1 axis modulator. These results provide new insights into the impact of exercise on AhR-signaling, which could potentially be relevant for various chronic diseases.

VO2peak Response Heterogeneity in Persons with Multiple Sclerosis: To HIIT or Not to HIIT?

Exercise is described to provoke enhancements of cardiorespiratory fitness in persons with Multiple Sclerosis (pwMS). However, a high inter-individual variability in training responses has been observed. This analysis investigates response heterogeneity in cardiorespiratory fitness following high intensity interval (HIIT) and moderate continuous training (MCT) and analyzes potential predictors of cardiorespiratory training effects in pwMS. 131 pwMS performed HIIT or MCT 3-5x/ week on a cycle ergometer for three weeks. Individual responses were classified. Finally, a multiple linear regression was conducted to examine potential associations between changes of absolute peak oxygen consumption (absolute ∆V̇O2peak/kg), training modality and participant's characteristics. Results show a time and interaction effect for ∆V̇O2peak/kg. Absolute changes of cardiorespiratory responses were larger and the non-response proportions smaller in HIIT vs. MCT. The model accounting for 8.6% of the variance of ∆V̇O2peak/kg suggests that HIIT, younger age and lower baseline fitness predict a higher absolute ∆V̇O2peak/kg following an exercise intervention. Thus, this work implements a novel approach that investigates potential determinants of cardiorespiratory response heterogeneity within a clinical setting and analyzes a remarkable bigger sample. Further predictors need to be identified to increase the knowledge about response heterogeneity, thereby supporting the development of individualized training recommendations for pwMS.

Cellular immune response to acute exercise: Comparison of endurance and resistance exercise.

OBJECTIVES: Exercise-induced cellular mobilization might play a role in treatment and prevention of several diseases. However, little is known about the impact of different exercise modalities on immune cell mobilization and clinical cellular inflammation markers. Therefore, the present study aimed to investigate differences between acute endurance exercise (EE) and resistance exercise (RE) on cellular immune alterations. METHODS: Twenty-four healthy men conducted an acute EE (cycling at 60% of peak power output) and RE (five exercise machines at 70% of the one-repetition maximum) session lasting 50 minutes in randomized order. Blood samples were collected before, after and one hour after exercise cessation. Outcomes included counts and proportions of leukocytes, neutrophils (NEUT), lymphocytes (LYM), LYM subsets, CD4/CD8 ratio, and the clinical cellular inflammation markers NEUT/LYM ratio (NLR), platelets/LYM ratio (PLR), and systemic immune inflammation index (SII). RESULTS: Alterations in all outcomes were revealed except for CD8+ T cells, CD4/CD8 ratio, NLR, and PLR. EE induced a stronger cellular immune response and provoked alterations in more immune cell populations than RE. SII was altered only after EE. CONCLUSION: An acute EE session causes a stronger mobilization of immune cells than RE. Additionally, SII represents an integrative marker to depict immunological alterations.

Exercise and the Kynurenine pathway: Current state of knowledge and results from a randomized cross-over study comparing acute effects of endurance and resistance training.

INTRODUCTION: The essential amino acid tryptophan (TRP) is primarily degraded through the kynurenine (KYN) pathway, which is dysregulated in several chronic diseases. KYN pathway metabolites have immune- and neuro-modulatory properties and are involved in th de novo synthesis of nicotinamide adenine dinucleotide (NAD+). Currently, little evidence exists demonstrating that physical exercise may influence this pathway. However, differences between acute and chronic stimuli as well as the influence of exercise modalities remain to be investigated. Here, we provide an overview of existing studies and present results of a randomized cross-over trial on acute effects of a single-bout of resistance and endurance exercise. METHODS: 24 healthy male adults conducted both an acute endurance exercise (EE) and resistance exercise (RE) session. Blood samples were collected before, immediately after and one hour after cessation of each exercise session. Outcomes comprised serum levels of TRP, KYN, kynurenic acid (KA), quinolinic acid (QA) and calculated ratios. Gene expression of the enzymes indoleamine 2,3 dioxygenase (IDO) 1 and kynurenine aminotransferase (KAT) 4 was measured in peripheral blood mononuclear cells (PBMCs). Moreover, serum concentrations of the potential KYN pathway mediators interleukin (IL)-6 and cortisol were determined. Finally, we investigated baseline correlations between immune cell subsets, potential mediators and initial KYN pathway activation outcomes. RESULTS: The KYN/TRP ratio correlated positively with IL-6 and CD56bright NK-cells and negatively with CD56dim NKcells. Expression of IDO1 in PBMCs correlated positively with IL-6, regulatory T-cells and CD56bright NK-cells, whereas negative correlations to cytotoxic T-cells and CD56dim NKcells were revealed. A significant time effect on KYN/TRP ratio was detected for RE. Regarding KA and KA/KYN ratio, an increase after exercise followed by a decrease at the follow- up measurement was revealed in EE. KAT4 expression also increased after exercise in EE. Moreover, elevated QA levels were observed after the EE session. CONCLUSIONS: In contrast to chronic exercise interventions, single-bouts of endurance exercise provoke acute alterations on KYN pathway outcomes in humans. Our results indicate that EE induces stronger alterations than RE. Enhanced conversion of KYN to both, KA and QA suggest a peripheral KYN clearance, thereby preventing pathological accumulation within the CNS. Future acute and chronic exercise studies are needed to examine the role of NAD+ synthesis starting with TRP and the interplay between KYN pathway activation and mid- to long-term immunological modulations.

Acute hypertrophic but not maximal strength loading transiently enhances the kynurenine pathway towards kynurenic acid.

PURPOSE: Due to distinct immuno- and neuro-modulatory properties, growing research interest focuses on exercise-induced alterations of the kynurenine (KYN) pathway in healthy and clinical populations. To date, knowledge about the impact of different acute strength exercise modalities on the KYN pathway is scarce. Therefore, we investigated the acute effects of hypertrophic (HYP) compared to maximal (MAX) strength loadings on the KYN pathway regulation. METHODS: Blood samples of twelve healthy males (mean age and weight: 23.5 ± 3.2 years; 77.5 ± 7.5 kg) were collected before (T0), immediately after (T1), and 1 h after completion (T2) of HYP (5 sets with 10 repetitions at 80% of 1RM) and MAX (15 sets with 1RM) loadings performed in a randomized cross-over design. Serum concentrations of tryptophan (TRP), KYN, kynurenic acid (KA), and quinolinic acid (QA) were assessed using high-performance liquid chromatography. RESULTS: The KA/KYN ratio increased from T0 to T1 (p = 0.01) and decreased from T1 to T2 (p = 0.011) in HYP, while it was maintained within MAX. Compared to MAX, serum concentrations of KA were greater in HYP at T1 (p = 0.014). Moreover, the QA/KA ratio was significantly lower in HYP than in MAX at T1 (p = 0.002). CONCLUSION: Acute HYP loading led to increases in the metabolic flux yielding KA, thereby possibly promoting immunosuppression and neuroprotection. Our findings emphasize the potential of acute HYP exercise as short-term modulator of KYN pathway downstream to KA in healthy males and need to be proven in other samples.

Influence of combined functional resistance and endurance exercise over 12 weeks on matrix metalloproteinase-2 serum concentration in persons with relapsing-remitting multiple sclerosis - a community-based randomized controlled trial.

BACKGROUND: The relevance of regular moderate to intense exercise for ameliorating psychomotor symptoms in persons with multiple sclerosis (pwMS) is becoming increasingly evident. Over the last two decades, emerging evidence from clinical studies and animal models indicate immune regulatory mechanisms in both periphery and the central nervous system that may underlie these beneficial effects. The integrity of the blood-brain barrier as the main structural interface between periphery and brain seems to play an important role in MS. Reducing the secretion of proteolytic matrix metalloproteinases (MMP), i.e. MMP-2, as disruptors of blood-brain barrier integrity could have profound implications for MS. METHODS: In this two-armed randomized controlled trial 64 participants with relapsing-remitting MS (RRMS) (EDSS 0-4.0) will be allocated to either an intervention group or a passive wait list control group. The intervention group will perform 60 min of combined functional resistance and endurance exercises 3x per week over a period of 12 weeks in a community-based and publicly available setting. Changes in serum concentration of MMP-2 will be the primary outcome. Secondary outcomes are numbers of immune cell subsets, soluble (anti-) inflammatory factors, physical capacity, cognitive performance, physical activity behavior, gait performance, and patient-reported outcomes. All outcome measures will be assessed at baseline and after week 12 with an additional blood sampling before, during and immediately after a single training session in week 6. DISCUSSION: To our knowledge, this will be the first RCT to investigate both the acute and chronic effects of a community-based intense functional resistance and endurance exercise regimen in persons with RRMS. Combining analysis of biological and cognitive or psychological outcomes may provide a better understanding of the MS-specific symptomology. TRIAL REGISTRATION: DRKS00017091; 05th of April, 2019; International Clinical Trials Registry Platform.

Influence of different rehabilitative aerobic exercise programs on (anti-) inflammatory immune signalling, cognitive and functional capacity in persons with MS - study protocol of a randomized controlled trial.

BACKGROUND: Studies have shown positive effects of therapeutic exercise on motor- and cognitive function as well as on psychosocial outcomes in persons with multiple sclerosis (MS). A reduction of inflammatory stress through physical exercise has been suspected as one key mechanism, mediating the positive effects of exercise in the context of MS. The primary objective of this trial is to investigate the acute and chronic effects of different exercise modalities on (anti-)inflammatory immune signalling as well as on cognitive and functional capacity in persons with MS. METHODS: A two armed single-blind randomized controlled design will investigate 72 persons with relapsing remitting or secondary progressive MS (EDSS 3.0-6.0), during 3 weeks of inpatient rehabilitation. Participants will be randomized into either a high-intensity interval training (HIIT) or a moderate continuous training group; the latter represents the local standard therapy (ST). Both groups will exercise 3x per week. The HIIT group will perform 5 × 1.5-min high-intensive exercise bouts at 95-100% of their maximum heart rate (HRmax) followed by active breaks of unloaded pedalling (60% HRmax) for 2 min. In contrast, the ST group will exercise for 24 min continuously at 65% of HRmax. The proportion of circulating regulatory T-cells will be measured as primary outcome. Secondary outcomes comprise numbers and proportions of further immune cells including Th17-cells, soluble factors ((anti-) inflammatory cytokines, tryptophan metabolites), endurance capacity, cognitive performance, processing skills for activities of daily living, fatigue, depression and healthcare-related quality of life. Outcomes will be assessed before (T0) and after (T3) the 3-week exercise intervention program. Blood samples of T0 will be taken immediately before the first exercise session. Additionally, blood samples for the soluble factors will be collected immediately after (T1) and three hours (T2) after the first exercise session of each group. DISCUSSION: This study will be the first to investigate both acute and chronic effects of aerobic exercise on immune function and disease associated biomarkers in persons with MS. Combining biological analyses with cognitive and functional capacity assessments may contribute to a better understanding of responses to rehabilitative training, needed to improve exercise recommendations for persons with MS. TRIAL REGISTRATION: This trial was prospectively registered at ClinicalTrials.gov ( NCT03652519 ; 29 August 2018).