HIIT Induces Stronger Shifts within the Peripheral T Cell Compartment Independent of Sex.

Acute exercise induces changes within the T-cell compartment, especially in cytotoxic CD8+ memory subsets, depending on exercise intensity and duration. It is unclear whether exercise-induced changes in major T-cell subsets differ in response to acute high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) and whether sex-specific effects exist. Twenty-four recreationally active runners (females: n=12, 27.8±4.1years, 54.4±4.6 ml*kg-1*min-1; males: n=12, 31.6±3.8years, 58.9±7.7 ml*kg-1*min-1) participated in this randomized controlled crossover study, and conducted an energy- and duration-matched HIIT and MICT session. Blood was sampled before (T1), immediately (T2) and 1 h after exercise (T3). Flow cytometry was used to identify T-cell populations. HIIT decreased the proportion of CD8+ T-cells more pronounced at T3 compared to MICT (p=0.007), induced a significantly stronger increase in the CD8+ effector memory (TEM) cell proportion at T2 (p=0.032), and decreased CD4+ central memory proportion more pronounced at T2 (p=0.029). A decrease below baseline CD8+ TEM proportion at T3 was observed only after HIIT (p<0.001). No interaction effects between sexes were revealed. Taken together, HIIT represents a more potent stimulus to induce shifts mainly within the cytotoxic CD8+ T-cell compartment, thereby giving implications to investigate the role of HIIT on the cell´s effector phenotype and function in more detail.

Impact of exercise on markers of B cell-related immunity: A systematic review.

BACKGROUND: B cells represent a crucial component of adaptive immunity that ensures long-term protection from infection by generating pathogen-specific immunoglobulins. Exercise alters B cell counts and immunoglobulin levels, but evidence-based conclusions on potential benefits for adaptive immunity are lacking. This systematic review assessed current literature on the impact of acute exercise and exercise training on B cells, immunoglobulins, and markers of secretory immunity in human biofluids. METHODS: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, MEDLINE, Web of Science, and Embase were searched on March 8, 2023. Non-randomized controlled trials and crossover trials investigating the impact of acute exercise or exercise training on B cell counts and proportions, immunoglobulin levels, salivary flow rate, or secretory immunoglobulin A secretion rate were included. Quality and reporting of exercise training studies was assessed using the Tool for the Assessment of Study Quality and reporting in Exercise. Study characteristics, outcome measures, and statistically significant changes were summarized tabularly. RESULTS: Of the 67 eligible studies, 22 applied acute exercise and 45 applied exercise training. All included outcomes revealed significant alterations over time in acute exercise and exercise training context, but only a few investigations showed significant differences compared to control conditions. Secretory and plasma immunoglobulin A levels were most consistently increased in response to exercise training. CONCLUSION: B cell-related outcomes are altered by acute exercise and exercise training, but evidence-based conclusions cannot be drawn with high confidence due to the large heterogeneity in populations and exercise modalities. Well-designed trials with large sample sizes are needed to clarify how exercise shapes B cell-related immunity.

Intensity- and time-matched acute interval and continuous endurance exercise similarly induce an anti-inflammatory environment in recreationally active runners: focus on PD-1 expression in Tregs and the IL-6/IL-10 axis.

PURPOSE: Acute exercise elicits a transient anti-inflammatory state during the early recovery period. Since recent studies reported on regimen-specific effects on immune-related humoral factors and cellular subsets, this study compared the effects of intensity- and time-matched acute interval and continuous exercise on peripheral anti-inflammatory cellular and humoral immune parameters with a particular focus on the PD-1 expression in CD4+ regulatory T cells (Tregs). METHODS: Twenty-four recreationally active runners (age: 29.7 ± 4.3 years, BMI: 22.2 ± 2.4, VO2peak: 56.6 ± 6.4 ml × kg-1 × min-1) participated in this crossover RCT. Each subject conducted a moderate continuous (MCE) and a high-intensity interval exercise (HIIE) session in a counterbalanced design. Blood was drawn before, immediately after, and 1 h after exercise. Treg subsets and levels of PD-1 and Foxp3 were assessed by flow cytometry. Serum levels of IL-10 and IL-6 were quantified by ELISA. RESULTS: PD-1 levels on Tregs increased within the recovery period after HIIE (p < .001) and MCE (p <  0.001). Total counts of Tregs (HIIE: p = 0.044; MCE: p = .021), naïve Tregs (HIIE: p  < 0.001; MCE: p  < 0.001), and PD-1+ effector Tregs (eTregs) (HIIE: p = .002) decreased 1 h after exercise. IL-10 increased 1 h after HIIE (p < 0.001) and MCE (p = 0.018), while IL-6 increased immediately after both HIIE (p = 0.031) and MCE (p = 0.021). Correlations between changes in IL-6 and IL-10 (p = 0.017, r = 0.379) and baseline VO2peak and Treg frequency (p = 0.002, r = 0.660) were identified. CONCLUSION: This is the first study that investigates PD-1 expression in circulating Tregs after acute exercise, revealing an increase in PD-1 levels on eTregs during the early recovery period after intensity- and time-matched HIIE and MCE. Future studies are needed to investigate the PD-1 signalosome in eTregs, together with the expression of key effector molecules (i.e., IL-10, TGF-ß, IL-35, CTLA-4) to elucidate PD-1-dependent changes in cellular function. Based on changes in serum cytokines, this study further reveals a regimen-independent establishment of an anti-inflammatory milieu and underpins the role of the IL-6/IL-10 axis.

The aerobic capacity - fatigue relationship in persons with Multiple Sclerosis is not reproducible in a pooled analysis of two randomized controlled trials.

BACKGROUND: Fatigue is one of the most frequent symptoms of persons with Multiple Sclerosis (pwMS) but has limited treatment options. Aerobic capacity and endurance training have been discussed as relevant factors to improve fatigue. However, over the last decades, results have been equivocal. This secondary analysis of two pooled parallel group RCTs of three weeks of endurance training (high intensity interval training (HIIT) and moderate continuous training (MCT)) for pwMS aimed to (I) reproduce reported associations between aerobic capacity and fatigue on a cross-sectional and interventional level. The analysis further aimed to (II) investigate intervention effects on fatigue in a severely fatigued subgroup and (III) analyze differences in changes of fatigue between peak oxygen uptake (VO2peak) responders and non-responders. METHODS: Both RCTs were conducted in the same inpatient rehabilitation clinic in Valens, Switzerland. Original primary outcomes were cognitive function (RCT1) and change in proportion of circulating regulatory T-cells (RCT2). PwMS (n = 131) with a relapsing-remitting or secondary progressive MS phenotype and Expanded Disability Status Scale score between 1 - 6.5 were eligible. Over the two studies participants exercised 3 - 5 times per week on cycle ergometers at intensities of 65 - 70% of maximum heart rate (HRmax) for 30 min (MCT groups) or three times per week with five 90 - 180 s intervals at intensities of 85% - 100% of HRmax and 90 s rest intervals (HIIT groups). Main outcome measures for the present secondary analysis were VO2peak measured during a cardiopulmonary exercise test and the Fatigue Scale for Motor and Cognitive Functions (FSMC), both assessed at the start and end of inpatient rehabilitation. RESULTS: Baseline correlations did not reveal a significant association between VO2peak and FSMC. There were no significant improvements in fatigue after the HIIT and MCT in the overall sample or the subsample of severely fatigued pwMS and no significant differences in fatigue changes between VO2peak-responders and non-responders. CONCLUSIONS: Our analysis did not confirm the aerobic capacity - fatigue relationship on a cross-sectional and experimental level, even when analyzing subgroups that should benefit the most according to proposed hypotheses.

Fitness, physical activity, and exercise in multiple sclerosis: a systematic review on current evidence for interactions with disease activity and progression.

BACKGROUND: A moderate to high level of physical activity, including regular exercise, represents an established behavioral and rehabilitative approach for persons with multiple sclerosis (pwMS). Although being increasingly proposed to limit disease activity and progression, high-quality evidence is lacking. OBJECTIVE: The objective of the study is to provide valuable information for MS clinicians and researchers by systematically evaluating the current state of evidence (i) whether exercise interventions affect established clinical measures of disease activity and progression in pwMS (i.e., EDSS, relapse rate, lesion load, brain volume, MSFC) and (ii) how the physical activity and fitness level interact with these measures. METHODS: Literature search was conducted in MEDLINE, EMBASE, CINAHL, and SPORTDiscus. Evaluation of evidence quality was done based on standards published by The American Academy of Neurology. RESULTS: It is likely that exercise improves the MSFC score, whereas the EDSS score, lesion load, and brain volume are likely to remain unchanged over the intervention period. It is possible that exercise decreases the relapse rate. Results from cross-sectional studies indicate beneficial effects of a high physical activity or fitness level on clinical measures which, however, is not corroborated by high evidence quality. CONCLUSIONS: A (supportive) disease-modifying effect of exercise in pwMS cannot be concluded. The rather low evidence quality of existing RCTs underlines the need to conduct more well-designed studies assessing different measures of disease activity or progression as primary end points. A major limitation is the short intervention duration of existing studies which limits meaningful exercise-induced effects on most disability measures. Findings from cross-sectional studies are difficult to contextualize regarding clinical importance due to their solely associative character and low evidence quality. PROSPERO REGISTRATION NUMBER: CRD42020188774.

The Molecular Signature of High-intensity Training in the Human Body.

High-intensity training is becoming increasingly popular outside of elite sport for health prevention and rehabilitation. This expanded application of high-intensity training in different populations requires a deeper understanding of its molecular signature in the human body. Therefore, in this integrative review, cellular and systemic molecular responses to high-intensity training are described for skeletal muscle, cardiovascular system, and the immune system as major effectors and targets of health and performance. Different kinds of stimuli and resulting homeostatic perturbations (i. e., metabolic, mechanical, neuronal, and hormonal) are reflected, taking into account their role in the local and systemic deflection of molecular sensors and mediators, and their role in tissue and organ adaptations. In skeletal muscle, a high metabolic perturbation induced by high-intensity training is the major stimulus for skeletal muscle adaptation. In the cardio-vascular system, high-intensity training induces haemodynamic stress and deflection of the Ca 2+ handling as major stimuli for functional and structural adaptation of the heart and vessels. For the immune system haemodynamic stress, hormones, exosomes, and O2 availability are proposed stimuli that mediate their effects by alteration of different signalling processes leading to local and systemic (anti)inflammatory responses. Overall, high-intensity training shows specific molecular signatures that demonstrate its high potential to improve health and physical performance.

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.

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.

Do baseline cognitive status, participant specific characteristics and EDSS impact changes of cognitive performance following aerobic exercise intervention in multiple sclerosis?

PURPOSE: Cognitive impairment is a common symptom of multiple sclerosis (MS). Physical exercise represents a promising non-pharmacological therapy option, however, potential predictors for successful cognitive improvements mediated by exercise remain to be elucidated in order to optimize targeted exercise training regimens. One of the most promising exercise training regime in this context is high-intensity interval training (HIIT). Against this backdrop, this study i) analysed the effects of a three-week HIIT compared to moderate continuous exercise on cognitive performance and ii) investigated potential predictors for changes of cognitive performance following a three-week aerobic exercise intervention. METHODS: Datasets of two randomized controlled trials (RCT) were pooled, resulting in a total sample size of n = 130 persons with MS (pwMS) who either performed HIIT or moderate intensity continuous (MCT) exercise 3-5x/ week for three weeks. Cognitive performance was assessed with the Brief International Cognitive Assessment for MS. I) Potential within (time) and interaction (time x group) effects for cognitive performance were investigated with univariate analyses of covariance (ANCOVA). II) Potential predictors for changes of cognitive performance were assessed by multiple linear regression models. RESULTS: ANCOVA revealed significant time effects for all cognitive outcomes and a time x group interaction for verbal learning (p=.045), with HIIT inducing superior effects compared to moderate continuous exercise (MCT). Cognitive status (impaired/intact cognition) (p= .008) and exercise regime (HIIT/moderate continuous) (p=.040) influenced changes of verbal learning. Cognitive status (p=.006) and EDSS (p=.048) affected changes of visuospatial memory in pwMS. The models accounted for 5.4% and 7.7% of the variance. CONCLUSION: Cognitive status, exercise regime and EDSS potentially impact changes of specific cognitive domains following aerobic exercise. Further predictors for changes of cognitive performance following an aerobic exercise intervention need to be investigated as current results accounted only for a limited amount of variance. RCTs that investigate effects of physical exercise on cognitive performance should include only pwMS with impaired baseline cognitive performance. To better understand the impact of exercise on cognitive performance, it is furthermore recommendable to include cognitive assessments in clinical routine.

Exercise Diminishes Plasma Neurofilament Light Chain and Reroutes the Kynurenine Pathway in Multiple Sclerosis.

OBJECTIVE: To examine acute (single-bout) and training effects of high-intensity interval training (HIIT) vs standard exercise therapy (moderate continuous training [MCT]) on plasma neurofilament light chain (pNfL) and kynurenine (KYN) pathway of tryptophan degradation metabolites in persons with multiple sclerosis (pwMS). METHODS: Sixty-nine pwMS (Expanded Disability Status Scale score 3.0-6.0) were randomly assigned to a HIIT or an MCT group. Changes in pNfL and KYN pathway metabolites measured in blood plasma were assessed before, after, and 3 hours after the first training session as well as after the 3-week training intervention. RESULTS: Acute exercise reduced pNfL and increased the KYN pathway flux toward the neuroprotective kynurenic acid (KA). Changes in pNfL correlated positively with changes in KA and negatively with the quinolinic acid-to-KA ratio. HIIT consistently led to greater effects than MCT. Following the 3-week training intervention, the KYN pathway was activated in HIIT compared with MCT. CONCLUSION: Future studies and clinical assessments of pNfL should consider acute exercise as confounding factor for measurement reliability. Moreover, exercise-induced KYN pathway rerouting might mediate neuroprotection, potentially underlying the benefits in rehabilitation for pwMS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that acute HIIT diminishes pNfL and increases KA levels, and 3 weeks of HIIT activate the KYN pathway in pwMS. TRIAL REGISTRATION INFORMATION: Clinical trial registration number: NCT03652519.

The Effect of Acute Physical Exercise on NK-Cell Cytolytic Activity: A Systematic Review and Meta-Analysis.

BACKGROUND: Data on changes in natural killer cell cytolytic activity (NKCA) in response to acute physical exercise are contradictory. OBJECTIVE: The aim of this systematic review, meta-analysis and meta-regression is to (1) examine the effect of acute physical exercise on NKCA, (2) shed more light on the moderating factors, and (3) test the assumption of NKCA suppression subsequent to performing sports. METHODS: Two comparisons of NKCA were performed: (1) pre- versus post-exercise and (2) pre-exercise versus recovery. Data were acquired through a systematic search of MEDLINE (via PubMed), Scopus, and SportDiscus. Studies were eligible for inclusion if the effect of acute physical exercise was assessed including a passive control group and reporting NKCA prior to and immediately after the trial, and during the first 2 h of recovery. To better explain between-study heterogeneity, a moderator analysis was conducted. RESULTS: Pooled estimate from 12 studies reporting 18 effect sizes show that NKCA is largely elevated by acute physical exercise (Hedges' g = 1.02, 95% CI 0.59-1.46, p < 0.01). Meta-regressions reveal that this effect is larger for endurance versus resistance exercise and increases with the intensity of exercise (both p < 0.01), whereas the blood material used in the assay (p = 0.71), and the quantitative change in NK-cell count (R2 = 0%, p = 0.55) do not play a significant role. Physical exercise does not affect the level of NKCA after the recovery period (g = 0.06, 95% CI - 0.37 to 0.50, p < 0.76). CONCLUSIONS: This work provides solid evidence for elevated NKCA through performing sports which returns to baseline during the first 1-2 h of recovery, but not below the pre-exercise values providing counterevidence to the assumption of temporarily reduced NKCA. Remarkably, the functional change in NKCA exists independently from the quantitative change in NK-cell count. PROSPERO registration number: CRD42020134257.

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.

Cognitive Impairment Impacts Exercise Effects on Cognition in Multiple Sclerosis.

Purpose: Exercise training reveals high potential to beneficially impact cognitive performance in persons with multiple sclerosis (pwMS). Research indicates that high-intensity interval training (HIIT) has potentially higher effects on physical fitness and cognition compared to moderate continuous exercise. This study (i) compares the effects of a 3-week HIIT and moderate continuous exercise training on cognitive performance and cardiorespiratory fitness of pwMS in an overall analysis and (ii) investigates potential effects based on baseline cognitive status in a subgroup analysis. Methods: Seventy-five pwMS were randomly assigned to an intervention (HIIT: 5 × 1.5-min intervals at 95-100% HRmax, 3 ×/week) or active control group (CG: 24 min continuous exercise at 65% HRmax, 3 ×/week). Cognitive performance was assessed pre- and post-intervention with the Brief International Cognitive Assessment for MS (BICAMS). (I) To examine potential within (time) and interaction (time × group) effects in the overall analysis, separate analyses of covariance (ANCOVA) were conducted. (II) For the subgroup analysis, participants were divided into two groups [intact cognition or impaired cognition (>1.5 standard deviation (SD) compared to healthy, age-matched norm data in at least one of the three tests of the BICAMS]. Potential impacts of cognitive status and intervention were investigated with multivariate analyses of variance (MANOVA). Results: Overall analysis revealed significant time effects for processing speed, verbal learning, rel. VO2peak, and rel. power output. A time*group interaction effect was observed for rel. power output. Subgroup analysis indicated a significant main effect for cognition (impaired cognition vs. intact cognition). Subsequent post-hoc analysis showed significant larger effects on verbal learning in pwMS with impaired cognition. Conclusion: Current results need to be confirmed in a powered randomized controlled trial with cognitive performance as primary endpoint and eligibility based on cognitive performance that is assessed prior to study inclusion.

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.

Neuroimmunological and neuroenergetic aspects in exercise-induced fatigue.

Feelings of fatigue not only occur in chronic and acute disease states, but also during prolonged strenuous exercise as a symptom of exhaustion. The underlying mechanisms of fatigue in diseases seem to rely on neuroinflammatory pathways. These pathways are interesting to understand exerciseinduced fatigue regarding immune system to brain signaling and effects of cerebral cytokines. Activation of the immune system incurs a high-energy cost, also in the brain. In consequence immune cells have high energetic priority over other tissues, such as neurons. A neuronal inactivation and corresponding changes in neurotransmission can also be induced by end products of ATP metabolism and elicit feelings of fatigue in diseases and after intensive and prolonged exercise bouts. Since there are no existing models of exercise-induced fatigue that specifically address interactions between neuroimmunologic mechanisms and neuroenergetics, this article is combining scientific evidence across a broad range of disciplines in order to propose an inflammation- and energy-based model for exercise-induced fatigue.