Beyond muscles: Investigating immunoregulatory myokines in acute resistance exercise - A systematic review and meta-analysis.

Myokines, released from the muscle, enable communication between the working muscles and other tissues. Their release during physical exercise is assumed to depend on immune-hormonal-metabolic interactions concerning mode (endurance or resistance exercise), duration, and intensity. This meta-analysis aims to examine the acute changes of circulating myokines inducing immunoregulatory effects caused by a bout of resistance exercise and to consider potential moderators of the results. Based on this selection strategy, a systematic literature search was conducted for resistance exercise intervention studies measuring interleukin (IL-) 6, IL-10, IL-1ra, tumor necrosis factor (TNF-) α, IL-15, IL-7, transforming growth factor (TGF-) ß1, and fractalkines (FKN) before and immediately after resistance exercise in healthy individuals. Random-effects meta-analysis was performed for each myokine. We identified a moderate positive effect of resistance exercise for IL-6 and IL-1ra. Regarding IL-15 and TNF-α, small to moderate effects were found. For IL-10, no significant effect was observed. Due to no data, meta-analyses for IL-7, TGF-ß1, and FKN could not be performed. No moderators (training status, type of exercise, risk of bias, age, sex, time of day, exercise volume, exercise intensity, exercise dose) of the results were detected for all tested myokines. Taken together, this systematic review and meta-analysis showed immediate positive effects of an acute resistance exercise session on IL-6, IL-1ra, TNF-α, and IL-15 levels.

Towards an understanding of physical activity-induced post-exertional malaise: Insights into microvascular alterations and immunometabolic interactions in post-COVID condition and myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: A considerable number of patients who contracted SARS-CoV-2 are affected by persistent multi-systemic symptoms, referred to as Post-COVID Condition (PCC). Post-exertional malaise (PEM) has been recognized as one of the most frequent manifestations of PCC and is a diagnostic criterion of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Yet, its underlying pathomechanisms remain poorly elucidated. PURPOSE AND METHODS: In this review, we describe current evidence indicating that key pathophysiological features of PCC and ME/CFS are involved in physical activity-induced PEM. RESULTS: Upon physical activity, affected patients exhibit a reduced systemic oxygen extraction and oxidative phosphorylation capacity. Accumulating evidence suggests that these are mediated by dysfunctions in mitochondrial capacities and microcirculation that are maintained by latent immune activation, conjointly impairing peripheral bioenergetics. Aggravating deficits in tissue perfusion and oxygen utilization during activities cause exertional intolerance that are frequently accompanied by tachycardia, dyspnea, early cessation of activity and elicit downstream metabolic effects. The accumulation of molecules such as lactate, reactive oxygen species or prostaglandins might trigger local and systemic immune activation. Subsequent intensification of bioenergetic inflexibilities, muscular ionic disturbances and modulation of central nervous system functions can lead to an exacerbation of existing pathologies and symptoms.

Acute effects of heavy resistance exercise on biomarkers of neuroendocrine-immune regulation in healthy adults: a systematic review.

BACKGROUND: The nervous system integrates the immune system in the systemic effort to maintain or restore the organism's homeostasis. Acute bouts of exercise may alter the activity of specific pathways associated with neuroendocrine regulation of the immune system. OBJECTIVE: To examine the acute effects of heavy resistance exercise on biomarkers of neuroendocrine-immune regulation in healthy adults. METHODS: A systematic literature search was conducted using PubMed, Cochrane Controlled Trials Register, Web of Science and SportDiscus with no date restrictions up to March 2021. Clinical trials in English or German were included if they measured the blood plasma or serum concentrations of specific biomarkers of neuroendocrine-immune regulation (adrenaline, noradrenaline, acetylcholine, vasoactive intestinal peptide (VIP), cortisol, growth hormone, calcitonin gene-related peptide (CGRP), substance p, serotonin, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) or glia-derived neurotrophic factor (GDNF)) in a resting state prior to and no later than 60 minutes after an acute bout of heavy resistance exercise in healthy adults. RESULTS: 7801 records were identified through literature search, of which 36 studies, with a total of 58 intervention groups, met the inclusion criteria. Evidence was found that an acute bout of heavy resistance exercise increased the levels of adrenaline (median: 185%), noradrenaline (median: 113%) and GH (median: 265%) immediately after the exercise. Mixed results were found for cortisol (median: 0%), suggesting that its response might be more sensitive to the configuration of the exercise scheme. The limited evidence regarding the effects on BDNF and ACTH allows no firm conclusions to be drawn about their response to heavy resistance exercise. The vast majority of the included studies reported a return of the biomarker concentrations to their baseline value within one hour after the termination of the exercise bout. No studies were identified that investigated the response of acetylcholine, VIP, CGRP, substance p, serotonin, NGF or GDNF to heavy resistance exercise. CONCLUSIONS: A bout of heavy resistance exercise alters the circulating concentrations of selected biomarkers of neuroendocrine-immune regulation. Both subject characteristics, such as sex as well as exercise parameters, such as rest intervals appear to have the potential to influence these effects.

The acute effects of pre- and mid-exercise carbohydrate ingestion on the immunoregulatory stress hormone release in experienced endurance athletes-a systematic review.

Background: In times of physical stress, the body orchestrates a multisystemic regulatory response. The hormones epinephrine and norepinephrine play a role in the immediate regulation chain, while cortisol is involved in delayed regulation. The release of those stress hormones in response to exercise has previously been reported to elicit diverse immune reactions. Objective: The aim of this systematic review was to examine and present the acute effects of immediate pre- and mid-exercise carbohydrate ingestion on cortisol, epinephrine and norepinephrine levels in experienced endurance athletes. Methods: A systematic literature search was conducted using PubMed, Cochrane Library and Web of Science in accordance with PRISMA guidelines up to February 2023. Randomized controlled trials in English or German language were included if baseline and at least two follow-up measures of blood plasma or serum of chosen stress hormones (cortisol, epinephrine, norepinephrine) were collected in response to prolonged continuous endurance activity. Eligibility furthermore required an acute carbohydrate ingestion of at least 30 g of carbohydrates per hour no more than 30 min before start of the exercise, as well as a placebo-controlled study design. Results: Eleven studies of moderate to high quality were included in this review. Carbohydrate ingestion of at least 30 g per hour was able to attenuate rises in cortisol concentration in majority of the included studies. Epinephrine levels were considerably lower with ingestion of carbohydrates compared to placebo in all studies. Norepinephrine concentrations were largely unaffected by acute carbohydrate feeding. Conclusion: Pre- and mid-exercise ingestion of carbohydrates seems an effective dietary strategy to attenuate rises in cortisol and epinephrine levels and, thus, an effective countermeasure for endurance exercise-induced increases in stress hormone levels.

T-cell-derived TNF-α and a cluster of immunological parameters from plasma allow a separation between SARS-CoV-2 convalescent versus vaccinated elite athletes.

Guidelines for medical clearing after SARS-CoV-2 infection in elite athletes do not include T-cell immunity aspects despite its relevance in the course of COVID-19 disease. Therefore, we aimed to analyze T-cell-related cytokines before and after in-vitro activation of CD4+ T-cells. We sampled professional indoor sports athletes at medical clearing after SARS-CoV-2 infection obtaining clinical, fitness data, and serological data including CD4+ T-cell cytokines. All data were analyzed by principal component analysis and 2 × 2 repeated measures ANOVA. CD4+ T-cells were sampled for cell culture activation with anti-CD3/anti-CD28 tetramers. At medical clearing, CD4+ T-cells from convalescent athletes secreted increased levels of TNF-α 72 h after in-vitro activation compared to vaccinated athletes. IL-18 levels in plasma were elevated and a cluster of parameters differentiated convalescent from vaccinated athletes by 13 parameters at the timepoint of medical clearing. All clinical data indicate infection is resolved, while increased TNF-α may reflect altered proportions of peripheral T-cells as a hangover of infection.

Long COVID: a narrative review of the clinical aftermaths of COVID-19 with a focus on the putative pathophysiology and aspects of physical activity.

The pandemic coronavirus disease 2019 (COVID-19) can cause multi-systemic symptoms that can persist beyond the acute symptomatic phase. The post-acute sequelae of COVID-19 (PASC), also referred to as long COVID, describe the persistence of symptoms and/or long-term complications beyond 4 weeks from the onset of the acute symptoms and are estimated to affect at least 20% of the individuals infected with SARS-CoV-2 regardless of their acute disease severity. The multi-faceted clinical picture of long COVID encompasses a plethora of undulating clinical manifestations impacting various body systems such as fatigue, headache, attention disorder, hair loss and exercise intolerance. The physiological response to exercise testing is characterized by a reduced aerobic capacity, cardiocirculatory limitations, dysfunctional breathing patterns and an impaired ability to extract and use oxygen. Still, to this day, the causative pathophysiological mechanisms of long COVID remain to be elucidated, with long-term organ damage, immune system dysregulation and endotheliopathy being among the hypotheses discussed. Likewise, there is still a paucity of treatment options and evidence-based strategies for the management of the symptoms. In sum, this review explores different aspects of long COVID and maps the literature on what is known about its clinical manifestations, potential pathophysiological mechanisms, and treatment options.

A scoping review of regulatory T cell dynamics in convalescent COVID-19 patients - indications for their potential involvement in the development of Long COVID?

Background: Recovery from coronavirus disease 2019 (COVID-19) can be impaired by the persistence of symptoms or new-onset health complications, commonly referred to as Long COVID. In a subset of patients, Long COVID is associated with immune system perturbations of unknown etiology, which could be related to compromised immunoregulatory mechanisms. Objective: The objective of this scoping review was to summarize the existing literature regarding the frequency and functionality of Tregs in convalescent COVID-19 patients and to explore indications for their potential involvement in the development of Long COVID. Design: A systematic search of studies investigating Tregs during COVID-19 convalescence was conducted on MEDLINE (via Pubmed) and Web of Science. Results: The literature search yielded 17 relevant studies, of which three included a distinct cohort of patients with Long COVID. The reviewed studies suggest that the Treg population of COVID-19 patients can reconstitute quantitatively and functionally during recovery. However, the comparison between recovered and seronegative controls revealed that an infection-induced dysregulation of the Treg compartment can be sustained for at least several months. The small number of studies investigating Tregs in Long COVID allowed no firm conclusions to be drawn about their involvement in the syndrome's etiology. Yet, even almost one year post-infection Long COVID patients exhibit significantly altered proportions of Tregs within the CD4+ T cell population. Conclusions: Persistent alterations in cell frequency in Long COVID patients indicate that Treg dysregulation might be linked to immune system-associated sequelae. Future studies should aim to address the association of Treg adaptations with different symptom clusters and blood parameters beyond the sole quantification of cell frequencies while adhering to consensualized phenotyping strategies.