Mild to moderate post-COVID-19 alters markers of lymphocyte activation, exhaustion, and immunometabolic responses that can be partially associated by physical activity level- an observational sub-analysis fit- COVID study.

Aim: This study aimed to evaluate if physical activity is associated with systemic and cellular immunometabolic responses, in young adults after mild-to-moderate COVID-19 infection. Methods: Mild- to- moderate post-COVID-19 patients (70.50 ± 43.10 days of diagnosis; age: 29.4 (21.9- 34.9) years; BMI: 25.5 ± 4.3 kg m2 n = 20) and healthy age-matched controls (age: 29.3 (21.2 - 32.6) years; BMI: 25.4 ± 4.7 kg m2; n = 20) were evaluated. Physical activity levels (PAL), body composition, dietary habits, muscular and pulmonary function, mental health, sleep quality, metabolic parameters, immune phenotypic characterization, stimulated whole blood and PBMC culture (cytokine production), mRNA, and mitochondrial respiration in PBMCs were evaluated. Results: The post-COVID-19 group exhibited lower levels of moderate to vigorous physical activity (MVPA) (p = 0.038); therefore, all study comparisons were performed with adjustment for MVPA. Post-COVID-19 impacted the pulmonary function (FEV1, FEV1%pred, FVC, and FVC %pred) compared with the control (p adjusted by MVPA (p adj) <0.05). Post-COVID-19 exhibited lower levels of serum IL-6 (p adj <0.01), whereas it showed higher serum IL-10, triglyceride, leptin, IgG, ACE activity, TNFRSF1A, and PGE2 (p adj <0.05) levels compared with controls. Post-COVID-19 presented a lower percentage of Treg cells (p adj = 0.03) and altered markers of lymphocyte activation and exhaustion (lower CD28 expression in CD8+ T cells (p adj = 0.014), whereas CD4+T cells showed higher PD1 expression (p adj = 0.037)) compared with the control group. Finally, post- COVID-19 presented an increased LPS-stimulated whole- blood IL-10 concentration (p adj <0.01). When exploring mitochondrial respiration and gene expression in PBMCs, we observed a higher LEAK state value (p adj <0.01), lower OXPHOS activity (complex I) (p adj = 0.04), and expression of the Rev-Erb-α clock mRNA after LPS stimulation in the post-COVID-19 patients than in the control (p adj <0.01). Mainly, PAL was associated with changes in IL-10, triglyceride, and leptin levels in the plasma of post-COVID-19 patients. PAL was also associated with modulation of the peripheral frequency of Treg cells and the expression of PD-1 in CD8+ T cells, although it abrogated the statistical effect in the analysis of TNF-α and IL-6 production by LPS- and PMA-stimulated PBMC of post-COVID-19 patients. Conclusion: Young adults after mild-to-moderate SARS-CoV-2 infection appeared to have lower physical activity levels, which can be associated with clinical and immunometabolic responses in a complex manner.

Saliva insulin tracks plasma insulin across the day following high-carbohydrate and low-carbohydrate meals.

Non-invasive monitoring of insulin could hold promise to identify those with, or at risk for developing, insulin resistance. We aimed to examine saliva insulin responses across the day following high- and low-carbohydrate meals and evaluate whether changes in saliva insulin might accurately reflect changes in plasma insulin. In two randomized crossover studies, young normal weight men (NW; n = 8; Study 1) and adults with overweight/obesity (OO; n = 8; Study 2) completed two 9-h experimental trials in which the participants consumed isocaloric mixed high-carbohydrate (HC) or low-carbohydrate (LC) meals at 0, 3, and 6 h. Plasma and saliva samples were collected at fasted baseline and every 30 min for a total of 19 samples across 9 h. Overall, findings revealed a similar trend for postprandial saliva and plasma insulin responses regardless of the time of the day with a ∼30-45 min lag between saliva and plasma insulin responses. In both NW and OO groups, saliva and plasma insulin area under the curve (AUC) and incremental AUC were significantly higher in HC condition as compared to LC condition (all P ≤ 0.002). Nine-hour plasma and saliva insulin total AUCs were strongly and very strongly correlated in both HC (r = 0.68; P = 0.007) and LC (r = 0.84, P < 0.001) conditions, respectively. Saliva insulin is proportionate to and appears to reasonably track plasma insulin across the day with a ∼30-45 min delay. Saliva insulin shows promise as a non-invasive method to discern between low and high plasma insulin and may have utility in predicting the degree of insulin resistance (NCT03374436).

Immunometabolism-fit: How exercise and training can modify T cell and macrophage metabolism in health and disease.

BACKGROUND: The term immunometabolism describes cellular and molecular metabolic processes that control the immune system and the associated immune responses. Acute exercise and regular physical activity have a substantial influence on the metabolism and the immune system, so that both processes are closely associated and influence each other bidirectionally. SCOPE OF REVIEW: We limit the review here to focus on metabolic phenotypes and metabolic plasticity of T cells and macrophages to describe the complex role of acute exercise stress and regular physical activity on these cell types. The metabolic and immunological consequences of the social problem of inactivity and how, conversely, an active lifestyle can break this vicious circle, are then described. Finally, these aspects are evaluated against the background of an aging society. MAJOR CONCLUSIONS: T cells and macrophages show high sensitivity to changes in their metabolic environment, which indirectly or directly affects their central functions. Physical activity and sedentary behaviour have an important influence on metabolic status, thereby modifying immune cell phenotypes and influencing immunological plasticity. A detailed understanding of the interactions between acute and chronic physical activity, sedentary behaviour, and the metabolic status of immune cells, can help to target the dysregulated immune system of people who live in a much too inactive society.

The Impact of Sub-maximal Exercise on Neuropathic Pain, Inflammation, and Affect Among Adults With Spinal Cord Injury: A Pilot Study.

Introduction: Persons with spinal cord injury (SCI) often report high levels of neuropathic pain (NP) and poor well-being, which may result from increased inflammation. This study examined the impact of sub-maximal aerobic exercise on NP, inflammation and psychological affect among adults with SCI. Methods: Eight active adults with tetraplegia (n-4, AIS A-C) and paraplegia (n = 4, AIS A-C) performed 30-min of arm-crank aerobic exercise and reported their ratings of perceived exertion (RPE) each minute. Measures of NP, affect, and inflammatory cytokines (IL-6, IL-10, IL-1ra, TNF-α) were taken pre-(T0), immediately post-(T1), and 90-min post-exercise (T2). Results: NP decreased between T0 and T1 for tetraplegics (-60%, d = 0.47; CI = -0.32, 2.02) and paraplegics (-16%, d = 0.15; CI = -0.30, 0.90). Correlations between change in cytokines and change in NP were medium-to large for tetraplegics (rs ranged from -0.820 to 0.965) and paraplegics (rs ranged from -0.598 to 0.833). However, the pattern of correlations between change in cytokines and affect was inconsistent between groups. Lower baseline levels of IL-1ra predicted greater decreases in NP immediately post-exercise (r = 0.83, p = 0.01). Conclusion: Sub-maximal exercise can positively impact NP for some persons with SCI. Further experimental research should identify the optimal exercise intensity to reduce NP for persons with SCI, in addition to understanding biomarkers which may predict changes in NP. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03955523.

Metabolic Effect of Breaking Up Prolonged Sitting with Stair Climbing Exercise Snacks.

PURPOSE: Prolonged sitting is associated with cardiometabolic complications. The study purpose was to investigate whether breaking up prolonged sitting with brief stair climbing exercise "snacks" could lower postprandial insulin, glucose, and free fatty acids responses. METHODS: In two separate randomized crossover studies, 12 young healthy-weight men (study 1) and 11 adults with overweight/obesity (OW; study 2) completed two experimental conditions: i) sedentary (SED; 9-h sitting) and ii) stair climbing snacks (SS; 8 × 15-30 s once per hour). The same high-glycemic index meals were consumed at 0, 3, and 6 h at each condition. The primary outcome was total insulin area under the curve (AUC) across 9 h. RESULTS: In healthy-weight men, there were no significant differences between SS and SED for total (9-h) insulin AUC (P = 0.24, d = 0.4), total glucose AUC (P = 0.17, d = 0.48), total nonesterified fatty acid (NEFA) AUC (P = 0.22, d = 0.4), or total triglyceride AUC (P = 0.72). In adults with OW, total insulin AUC (-16.5%, P = 0.036, d = 0.94) and total NEFA AUC (-21%, P = 0.016, d = 1.2) were significantly lower in SS versus SED. No differences were found for total glucose and triglyceride AUC (all, P > 0.31) in participants with OW. CONCLUSIONS: Breaking up 9 h of prolonged sitting with hourly brief stair climbing exercise snacks lowered postprandial insulin and NEFA levels in adults with overweight/obesity.

Correction: A pragmatic randomized controlled trial testing the effects of the international scientific SCI exercise guidelines on SCI chronic pain: protocol for the EPIC-SCI trial.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The effect of low-volume high-intensity interval training on cardiometabolic health and psychological responses in overweight/obese middle-aged men.

High-intensity interval training (HIIT) has been proposed as a time-efficient exercise protocol to improve metabolic health, but direct comparisons with higher-volume moderate-intensity continuous training (MICT) under unsupervised settings are limited. This study compared low-volume HIIT and higher-volume MICT interventions on cardiometabolic and psychological responses in overweight/obese middle-aged men. Twenty-four participants (age: 48.1±5.2yr; BMI: 25.8±2.3kg·m-2) were randomly assigned to undertake either HIIT (10 X 1-min bouts of running at 80-90% HRmax separated by 1-min active recovery) or MICT (50-min continuous jogging/brisk walking at 65-70% HRmax) for 3 sessions/week for 8 weeks (2-week supervised + 6-week unsupervised training). Both groups showed similar cardiovascular fitness (VO2max) improvement (HIIT: 32.5±5.6 to 36.0±6.2; MICT: 34.3±6.0 to 38.2±5.1mL kg-1 min-1, p < 0.05) and %fat loss (HIIT: 24.5±3.4 to 23.2±3.5%; MICT: 23.0±4.3 to 21.5±4.1%, p< 0.05) over the 8-week intervention. Compared to baseline, MICT significantly decreased weight and waist circumference. No significant group differences were observed for blood pressure and cardiometabolic blood markers such as lipid profiles, fasting glucose and glycated haemoglobin. Both groups showed similar enjoyment levels and high unsupervised adherence rates (>90%). Our findings suggest that low-volume HIIT can elicit a similar improvement of cardiovascular fitness as traditional higher-volume MICT in overweight/obese middle-aged men.

A pragmatic randomized controlled trial testing the effects of the international scientific SCI exercise guidelines on SCI chronic pain: protocol for the EPIC-SCI trial.

STUDY DESIGN: Protocol for a pragmatic randomized controlled trial (the Exercise guideline Promotion and Implementation in Chronic SCI [EPIC-SCI] Trial). PRIMARY OBJECTIVES: To test if home-/community-based exercise, prescribed according to the international SCI exercise guidelines, significantly reduces chronic bodily pain in adults with SCI. SECONDARY OBJECTIVES: To investigate: (1) the effects of exercise on musculoskeletal and neuropathic chronic pain; (2) if reduced inflammation and increased descending inhibitory control are viable pathways by which exercise reduces pain; (3) the effects of chronic pain reductions on subjective well-being; and (4) efficiency of a home-/community-based exercise intervention. SETTING: Exercise in home-/community-based settings; assessments in university-based laboratories in British Columbia, Canada. METHOD: Eighty-four adults with chronic SCI, reporting chronic musculoskeletal or neuropathic pain, and not meeting the current SCI exercise guidelines, will be recruited and randomized to a 6-month Exercise or Wait-List Control condition. Exercise will occur in home/community settings and will be supported through behavioral counseling. All measures will be taken at baseline, 3-months and 6-months. Analyses will consist of linear mixed effect models, multiple regression analyses and a cost-utility analysis. The economic evaluation will examine the incremental costs and health benefits generated by the intervention compared with usual care. ETHICS AND DISSEMINATION: The University of British Columbia Clinical Research Ethics Board approved the protocol (#H19-01650). Using an integrated knowledge translation approach, stakeholders will be engaged throughout the trial and will co-create and disseminate evidence-based recommendations and messages regarding the use of exercise to manage SCI chronic pain.

High- or moderate-intensity training promotes change in cardiorespiratory fitness, but not visceral fat, in obese men: A randomised trial of equal energy expenditure exercise.

This study compared the effects of two exercise programs performed in different intensities, but equal overall energy expenditure (EE). Adult men with obesity (29.6 ± 4.9 years; BMI = 35.1 ± 3.3 kg/m2) were randomised to one of three groups: High-intensity interval training (HIIT- 10 × 1:1 min 100% VO2max; n = 13); Moderate-intensity continuous training (MICT - ˜35 min 65% VO2max; n = 13) or Control (no training; n = 6). The session EE (HIIT = 278.0 ± 37.1; MICT = 299.4 ± 17.8 kcal) was calculated by adding the aerobic contribution (VO2 of the session minus VO2 at rest) and anaerobic (difference between the VO2 estimated and VO2 measured in session). The anaerobic contribution in HIIT was 30%, showing that a substantial portion of the energy for 10 x 1 min HIIT comes from non-oxidative metabolism. VO2max improved in both trained groups (p = 0.006), while systolic blood pressure decreased (p < 0.001) and diastolic blood pressure was not altered. Visceral and subcutaneous fat stores did not change after the intervention, indicating a longer intervention may be necessary for changes in adiposity. Six weeks of HIIT or MICT were effective in improving cardiorespiratory fitness and blood pressure in previously inactive obese men.

Short-term exercise training reduces glycaemic variability and lowers circulating endothelial microparticles in overweight and obese women at elevated risk of type 2 diabetes.

Exercise is recognized as a frontline therapy for the prevention and treatment of type 2 diabetes (T2D) but the optimal type of exercise is not yet determined. We compared the effects of high-intensity interval training (HIIT) with moderate-intensity continuous training (MICT) for improvement of continuous glucose monitoring (CGM)-derived markers of glycaemic variability, and biomarkers of endothelial cell damage (CD31+ and CD62+ endothelial microparticles (EMPs)) within a population at elevated risk of developing T2D. Fifteen inactive overweight or obese women were randomized to 2 weeks (10-sessions) of progressive HIIT (n = 8, 4-10X 1-min @ ∼90% peak heart rate, 1-min rest periods) or MICT (n = 7, 20-50 min of continuous activity at ∼65% peak heart rate). Prior and three days post-training, fasting blood samples were collected. Both HIIT and MICT improved glycaemic variability as measured by CGM standard deviation (HIIT: 0.82 ± 0.39 vs. 0.72 ± 0.33 mmol/L; MICT: 0.82 ± 0.19 vs. 0.62 ± 0.16 mmol/L, pre vs. post) and mean amplitude of glycaemic excursions (MAGE; HIIT: 1.98 ± 0.81 vs. 1.41 ± 0.90; MICT; 1.98 ± 0.43 vs. 1.65 ± 0.48, pre vs. post) with no difference between groups. CD62+ EMPs were lower following HIIT (187.7 ± 65 vs. 174.9 ± 55, pre vs. post) and MICT (170 ± 60 vs. 160.3 ± 59, pre vs. post) with no difference between groups. There was no change in 24-h mean glucose or CD31+ EMPs. Two weeks of both HIIT or MICT similarly decreased glycaemic variability and CD62+ EMPs in overweight/obese women at elevated risk of T2D.

Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals.

KEY POINTS: The recent development of exogenous ketone supplements allows direct testing of the metabolic effects of elevated blood ketones without the confounding influence of widespread changes experienced with ketogenic diets or prolonged fasting. In the present study, we determined the effect of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone monoester on the glycaemic response and insulin sensitivity index during a 2 h oral glucose tolerance test (OGTT) in humans. The results obtained show that consuming a ketone monoester supplement 30 min prior to an OGTT reduced the glycaemic response and markers of insulin sensitivity without affecting insulin secretion. The findings of the present study provides evidence that ketone supplements could have therapeutic potential for future application as a glucose-lowering nutritional supplement. ABSTRACT: The main objectives of the present study were: (i) to determine whether acute ingestion of ketone monoester (Kme ); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate impacts plasma glucose levels during a standardized oral glucose tolerance test (OGTT) and (ii) to compare changes in insulin concentrations and estimates of insulin sensitivity after acute Kme supplementation. Twenty healthy participants (n = 10 males/females) aged between 18 and 35 years took part in a randomized cross-over study. After an overnight fast, participants consumed a Kme supplement (ΔG®; TΔS Ltd, UK, Oxford, UK; 0.45 ml kg-1 body weight) or placebo (water) 30 min before completing a 75 g OGTT. Blood samples were collected every 15-30 min over 2.5 h. The participants and study personnel performing the laboratory analyses were blinded to the study condition. Kme acutely raised blood d-beta-hydroxybutyrate (ß-OHB) to 3.2 ± 0.6 mm within 30 min with levels remaining elevated throughout the entire OGTT. Compared to placebo, Kme significantly decreased the glucose area under the curve (AUC; -17%, P = 0.001), non-esterified fatty acid AUC (-44%, P < 0.001) and C-peptide incremental AUC (P = 0.005), at the same time as improving oral glucose insulin sensitivity index by ∼11% (P = 0.001). In conclusion, a Kme supplement that acutely increased ß-OHB levels up to ∼3 mm attenuated the glycaemic response to an OGTT in healthy humans. The reduction in glycaemic response did not appear to be driven by an increase in insulin secretion, although it was accompanied by improved markers of insulin sensitivity. These results suggest that ketone monoester supplements could have therapeutic potential in the management and prevention of metabolic diseases.

Detection of Salivary Insulin Following Low versus High Carbohydrate Meals in Humans.

Developing non-invasive alternatives to monitor insulin levels in humans holds potential practical value for identifying individuals with, or at risk of developing, insulin resistance. The aims of this study were: (1) to determine if saliva insulin can be used to delineate between low and high postprandial insulin levels following the ingestion of mixed breakfast meals; and (2) to determine if expected differences in postprandial hyperinsulinemia between young lean and young overweight/obese participants could be detected in saliva. Sixteen individuals (n = 8 classified as normal weight (NW); BMI 20.0-24.9 kg/m², and n = 8 classified as overweight/obese (OO); BMI ≥ 28.0 kg/m²) completed two isocaloric mixed-meal tolerance tests following an overnight fast, consisting of a low-carbohydrate (LC) breakfast or a high-carbohydrate (HC) breakfast. Blood and saliva samples were collected at regular intervals for two hours postprandially. In both groups, plasma and saliva insulin total area under the curve (AUC) and incremental AUC (iAUC) were significantly higher after the HC as compared to the LC meal (all p ≤ 0.005). Insulin AUC and iAUC in both plasma and saliva were higher in OO than in NW after the HC meal (all p ≤ 0.02) but only plasma and saliva total AUC were higher in OO after the LC meal (both p ≤ 0.01). Plasma insulin AUC was significantly correlated with salivary insulin AUC in LC (r = 0.821; p < 0.001) and HC (r = 0.882; p < 0.001). These findings indicate that saliva could potentially be used to delineate between low and high insulin levels following mixed breakfast meals.

Physical activity and exercise attenuate neuroinflammation in neurological diseases.

Major depressive disorder (MDD), schizophrenia (SCH), Alzheimer's disease (AD), and Parkinson's disease (PD) are devastating neurological disorders, which increasingly contribute to global morbidity and mortality. Although the pathogenic mechanisms of these conditions are quite diverse, chronic neuroinflammation is one underlying feature shared by all these diseases. Even though the specific root causes of these diseases remain to be identified, evidence indicates that the observed neuroinflammation is initiated by unique pathological features associated with each specific disease. If the initial acute inflammation is not resolved, a chronic neuroinflammatory state develops and ultimately contributes to disease progression. Chronic neuroinflammation is characterized by adverse and non-specific activation of glial cells, which can lead to collateral damage of nearby neurons and other glia. This misdirected neuroinflammatory response is hypothesized to contribute to neuropathology in MDD, SCH, AD, and PD. Physical activity (PA), which is critical for maintenance of whole body and brain health, may also beneficially modify neuroimmune responses. Since PA has neuroimmune-modifying properties, and the common underlying feature of MDD, SCH, AD, and PD is chronic neuroinflammation, we hypothesize that PA could minimize brain diseases by modifying glia-mediated neuroinflammation. This review highlights current evidence supporting the disease-altering potential of PA and exercise through modifications of neuroimmune responses, specifically in MDD, SCH, AD and PD.