Exercise Training and Circulating Small Extracellular Vesicles: Appraisal of Methodological Approaches and Current Knowledge

In response to acute exercise, an array of metabolites, nucleic acids, and proteins are enriched in circulation. Collectively termed “exercise factors,” these molecules represent a topical area of research given their speculated contribution to both acute exercise metabolism and adaptation to exercise training. In addition to acute changes induced by exercise, the resting profile of circulating exercise factors may be altered by exercise training. Many exercise factors are speculated to be transported in circulation as the cargo of extracellular vesicles (EVs), and in particular, a sub-category termed “small EVs.” This review describes an overview of exercise factors, small EVs and the effects of exercise, but is specifically focused on a critical appraisal of methodological approaches and current knowledge in the context of changes in the resting profile small EVs induced by exercise training, and the potential bioactivities of preparations of these “exercise-trained” small EVs. Research to date can only be considered preliminary, with interpretation of many studies hindered by limited evidence for the rigorous identification of small EVs, and the conflation of acute and chronic responses to exercise due to sample timing in proximity to exercise. Further research that places a greater emphasis on the rigorous identification of small EVs, and interrogation of potential bioactivity is required to establish more detailed descriptions of the response of small EVs to exercise training, and consequent effects on exercise adaptation.

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Exercise adaptation attenuates VEGF gene expression in human skeletal muscle

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.2.h772 ◽

2000 ◽

Vol 279 (2) ◽

pp. H772-H778 ◽

Cited By ~ 93

Author(s):

R. S. Richardson ◽

H. Wagner ◽

S. R. D. Mudaliar ◽

E. Saucedo ◽

R. Henry ◽

...

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Human Skeletal Muscle ◽

Acute Exercise ◽

Vastus Lateralis ◽

Northern Analysis ◽

Endothelial Cell Proliferation ◽

Vastus Lateralis Muscle ◽

Mrna Levels ◽

Exercise Adaptation

Angiogenesis is a component of the multifactoral adaptation to exercise training, and vascular endothelial growth factor (VEGF) is involved in extracellular matrix changes and endothelial cell proliferation. However, there is limited evidence supporting the role of VEGF in the exercise training response. Thus we studied mRNA levels of VEGF, using quantitative Northern analysis, in untrained and trained human skeletal muscle at rest and after a single bout of exercise. Single leg knee-extension provided the acute exercise stimulus and the training modality. Four biopsies were collected from the vastus lateralis muscle at rest in the untrained and trained conditions before and after exercise. Training resulted in a 35% increase in muscle oxygen consumption and an 18% increase in number of capillaries per muscle fiber. At rest, VEGF/18S mRNA levels were similar before (0.38 ± 0.04) and after (1.2 ± 0.4) training. When muscle was untrained, acute exercise greatly elevated VEGF/18S mRNA levels (16.9 ± 6.7). The VEGF/18S mRNA response to acute exercise in the trained state was markedly attenuated (5.4 ± 1.3). These data support the concept that VEGF is involved in exercise-induced skeletal muscle angiogenesis and appears to be subject to a negative feedback mechanism as exercise adaptations occur.

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The effect of an acute exercise bout on plasme miRNA and its relation with cardiovascular adaptation to exercise training in heart failure

European Heart Journal ◽

10.1093/ehjci/ehaa946.1074 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

I Witvrouwen ◽

E Boeren ◽

N Possemiers ◽

W Hens ◽

P.J Beckers ◽

...

Keyword(s):

Heart Failure ◽

Exercise Training ◽

Ejection Fraction ◽

Aerobic Capacity ◽

Vascular Function ◽

Acute Exercise ◽

Exercise Bout ◽

Funding Source ◽

Percent Change ◽

Adaptation To Exercise

Abstract Background Exercise training (ET) improves aerobic capacity (VO2peak) in heart failure with reduced ejection fraction (HFrEF), but the individual response is highly variable. Underlying mechanisms of this variability are still not fully elucidated yet. Specific miRNA might be involved in cardiovascular adaptation to exercise, as changes in miRNA levels with repetitive acute exercise bouts have been described. miR-23a, -140, -146a, -191 and -210 have been related to aerobic capacity, endothelial function and angiogenesis. Purpose First, to evaluate if vascular function-associated miRNAs are related to vascular function and aerobic capacity in HFrEF patients. Second, to evaluate the effect of a single exercise bout on the miR profile. Third, to evaluate if miRNA changes in response to acute exercise are related to aerobic and vascular response to training. Methods Plasma levels of miR-23a, -140, -146a, -191 and -210 were analyzed using RT-qPCR in 24 HFrEF patients, before and immediately after a cardiopulmonary exercise test (CPET) and repeated after 15 weeks of ET. At baseline and after 15 weeks, VO2peak, flow-mediated dilation (FMD), pulsed wave velocity (PWV) and heart rate-corrected augmentation index (Aix@75) were recorded. Results In this prospective study, 24 HFrEF patients were included. Mean age was 56.9±12.9 years, mean left ventricular ejection fraction 31.7±7.0% and median adherence to ET was 41 sessions (30–43). Mean percent change in VO2peak was 2.86% (±13.5), in Aix@75 −9.8% (±80.9), in FMD 79.1% (±223.7) and in PWV −3.1% (±11.2), however these changes were not significant compared to baseline (p>0.05). At baseline, none of the miRNA were correlated with percent change in VO2peak (all p>0.05), however, miR-140 showed a trend towards correlation (r=−0.385, p=0.063). miR-191was significantly correlated with Aix@75 at baseline and after 15 weeks (respectively r=0.588, p=0.013 and r=0.609, p=0.006) and miR-23a was significantly correlated with FMD at baseline and showed a trend at 15 weeks (respectively r=0.462, p=0.040 and r=0.417, p=0.076). An acute exercise bout resulted in a significant decrease of miR-191 (1.82 before and 1.58 after CPET; 14% decrease, p=0.043). This change was significantly correlated with percent change in Aix@75 (r=−0.730, p=0.005) after ET. In a linear regression model adjusted for age, change in miR-191 significantly predicted percent change in Aix@75 (B=−84.5, p=0.043). Conclusion In HFrEF patients, plasma levels of miR-191 significantly decrease in response to an acute exercise bout. Baseline levels of vascular function-associated miRNAs were correlated with arterial stiffness and endothelial function before and after exercise training, which may suggest that these miRNAs are implicated in the vascular adaptations due to repetitive acute exercise bouts. However, these findings need to be validated in larger cohorts. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Fund for scientific research-Flanders (FWO)

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Plasma levels of microRNA in chronic kidney disease: patterns in acute and chronic exercise

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00346.2015 ◽

2015 ◽

Vol 309 (12) ◽

pp. H2008-H2016 ◽

Cited By ~ 24

Author(s):

Amaryllis H. Van Craenenbroeck ◽

Kristien J. Ledeganck ◽

Katrijn Van Ackeren ◽

Angelika Jürgens ◽

Vicky Y. Hoymans ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Exercise Training ◽

Plasma Levels ◽

Acute Exercise ◽

Physiological Role ◽

Fold Change ◽

Chronic Exercise ◽

Exercise Induced ◽

Adaptation To Exercise

Exercise training is an effective way to improve exercise capacity in chronic kidney disease (CKD), but the underlying mechanisms are only partly understood. In healthy subjects (HS), microRNA (miRNA or miR) are dynamically regulated following exercise and have, therefore, been suggested as regulators of cardiovascular adaptation to exercise. However, these effects were not studied in CKD before. The effect of acute exercise (i.e., an acute exercise bout) was assessed in 32 patients with CKD and 12 age- and sex-matched HS ( study 1). miRNA expression in response to chronic exercise (i.e., a 3-mo exercise training program) was evaluated in 40 CKD patients ( study 2). In a subgroup of study 2, the acute-exercise induced effect was evaluated at baseline and at follow-up. Plasma levels of a preselected panel miRNA, involved in exercise adaptation processes such as angiogenesis (miR-126, miR-210), inflammation (miR-21, miR-146a), hypoxia/ischemia (miR-21, miR-210), and progenitor cells (miR-150), were quantified by RT-PCR. Additionally, seven miRNA involved in similar biological processes were quantified in the subgroup of study 2. Baseline, studied miRNA were comparable in CKD and HS. Following acute exercise, miR-150 levels increased in both CKD (fold change 2.12 ± 0.39, P = 0.002; and HS: fold change 2.41 ± 0.48 P = 0.018, P for interaction > 0.05). miR-146a acutely decreased in CKD (fold change 0.92 ± 0.13, P = 0.024), whereas it remained unchanged in HS. Levels of miR-21, miR-126, and miR-210 remained unaltered. Chronic exercise did not elicit a significant change in the studied miRNA levels. However, an acute exercise-induced decrease in miR-210 was observed in CKD patients, only after training (fold change 0.76 ± 0.15). The differential expression in circulating miRNA in response to acute and chronic exercise may point toward a physiological role in cardiovascular adaptation to exercise, also in CKD.

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Urinary Extracellular Vesicles for Diabetic Kidney Disease Diagnosis

Journal of Clinical Medicine ◽

10.3390/jcm10102046 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2046

Author(s):

Goren Saenz-Pipaon ◽

Saioa Echeverria ◽

Josune Orbe ◽

Carmen Roncal

Keyword(s):

Kidney Disease ◽

Extracellular Vesicles ◽

Diabetic Kidney Disease ◽

Current Knowledge ◽

Developed Countries ◽

Disease Diagnosis ◽

Renal Diseases ◽

Diabetic Kidney ◽

Glucose Levels ◽

Stage Renal Disease

Diabetic kidney disease (DKD) is the leading cause of end stage renal disease (ESRD) in developed countries, affecting more than 40% of diabetes mellitus (DM) patients. DKD pathogenesis is multifactorial leading to a clinical presentation characterized by proteinuria, hypertension, and a gradual reduction in kidney function, accompanied by a high incidence of cardiovascular (CV) events and mortality. Unlike other diabetes-related complications, DKD prevalence has failed to decline over the past 30 years, becoming a growing socioeconomic burden. Treatments controlling glucose levels, albuminuria and blood pressure may slow down DKD evolution and reduce CV events, but are not able to completely halt its progression. Moreover, one in five patients with diabetes develop DKD in the absence of albuminuria, and in others nephropathy goes unrecognized at the time of diagnosis, urging to find novel noninvasive and more precise early diagnosis and prognosis biomarkers and therapeutic targets for these patient subgroups. Extracellular vesicles (EVs), especially urinary (u)EVs, have emerged as an alternative for this purpose, as changes in their numbers and composition have been reported in clinical conditions involving DM and renal diseases. In this review, we will summarize the current knowledge on the role of (u)EVs in DKD.

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Extracellular vesicles and leishmaniasis: Current knowledge and promising avenues for future development

Molecular Immunology ◽

10.1016/j.molimm.2021.04.003 ◽

2021 ◽

Vol 135 ◽

pp. 73-83

Author(s):

George Dong ◽

Victoria Wagner ◽

Aida Minguez-Menendez ◽

Christopher Fernandez-Prada ◽

Martin Olivier

Keyword(s):

Extracellular Vesicles ◽

Future Development ◽

Current Knowledge

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The Therapeutic Effect of Extracellular Vesicles on Asthma in Pre-Clinical Models: A Systematic Review Protocol

Journal of Respiration ◽

10.3390/jor1010009 ◽

2021 ◽

Vol 1 (1) ◽

pp. 84-95

Author(s):

Patience O. Obi ◽

Jennifer E. Kent ◽

Maya M. Jeyaraman ◽

Nicole Askin ◽

Taiana M. Pierdoná ◽

...

Keyword(s):

Systematic Review ◽

Extracellular Vesicles ◽

Current Knowledge ◽

Grey Literature ◽

Specific Treatment ◽

Therapeutic Effects ◽

Management Options ◽

Paracrine Signalling

Asthma is the most common pediatric disease, characterized by chronic airway inflammation and airway hyperresponsiveness. There are several management options for asthma, but no specific treatment. Extracellular vesicles (EVs) are powerful cellular mediators of endocrine, autocrine and paracrine signalling, and can modulate biophysiological function in vitro and in vivo. A thorough investigation of therapeutic effects of EVs in asthma has not been conducted. Therefore, this systematic review is designed to synthesize recent literature on the therapeutic effects of EVs on physiological and biological outcomes of asthma in pre-clinical studies. An electronic search of Web of Science, EMBASE, MEDLINE, and Scopus will be conducted on manuscripts published in the last five years that adhere to standardized guidelines for EV research. Grey literature will also be included. Two reviewers will independently screen the selected studies for title and abstract, and full text based on the eligibility criteria. Data will be extracted, narratively synthesized and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This systematic review will summarize the current knowledge from preclinical studies investigating the therapeutic effects of EVs on asthma. The results will delineate whether EVs can mitigate biological hallmarks of asthma, and if so, describe the underlying mechanisms involved in the process. This insight is crucial for identifying key pathways that can be targeted to alleviate the burden of asthma. The data will also reveal the origin, dosage and biophysical characteristics of beneficial EVs. Overall, our results will provide a scaffold for future intervention and translational studies on asthma treatment.

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The Creation of a Mental Health Policy in Higher Education

Educational Policy ◽

10.1177/08959048211015613 ◽

2021 ◽

pp. 089590482110156

Author(s):

Kelly A. Pilato ◽

Madelyn P. Law ◽

Miya Narushima ◽

Shannon A. Moore ◽

John A. Hay

Keyword(s):

Critical Appraisal ◽

Mental Health Policy ◽

Student Voices ◽

Limited Evidence ◽

Comprehensive University ◽

Qualitative And Quantitative ◽

Student Union ◽

The Creation ◽

Mental Wellness

The mental wellness of university students can be critical for their success. In an attempt to minimize stress for students, many universities have implemented a policy for a fall break with limited evidence to support its intended outcomes. This case study offers a critical appraisal of the formation of the fall break policy at one medium sized comprehensive university using qualitative and quantitative forms of evidence triangulated from (1) University Student Union survey, (2) document analysis and; (3) informant interview. The lack of uniformity on how the fall break is labelled, the timing of the break and its evaluation emerged as design flaws in the creation stage that perhaps, could have been mitigated if faculty and student voices were included in policy creation decisions.

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Cell-to-Cell Communication by Host-Released Extracellular Vesicles in the Gut: Implications in Health and Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22042213 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2213

Author(s):

Natalia Diaz-Garrido ◽

Cecilia Cordero ◽

Yenifer Olivo-Martinez ◽

Josefa Badia ◽

Laura Baldomà

Keyword(s):

Extracellular Vesicles ◽

Intestinal Mucosa ◽

Current Knowledge ◽

Cell Communication ◽

Bioactive Molecules ◽

Target Cells ◽

Immune Functions ◽

Intestinal Homeostasis ◽

General Terms ◽

Health And Disease

Communication between cells is crucial to preserve body homeostasis and health. Tightly controlled intercellular dialog is particularly relevant in the gut, where cells of the intestinal mucosa are constantly exposed to millions of microbes that have great impact on intestinal homeostasis by controlling barrier and immune functions. Recent knowledge involves extracellular vesicles (EVs) as mediators of such communication by transferring messenger bioactive molecules including proteins, lipids, and miRNAs between cells and tissues. The specific functions of EVs principally depend on the internal cargo, which upon delivery to target cells trigger signal events that modulate cellular functions. The vesicular cargo is greatly influenced by genetic, pathological, and environmental factors. This finding provides the basis for investigating potential clinical applications of EVs as therapeutic targets or diagnostic biomarkers. Here, we review current knowledge on the biogenesis and cargo composition of EVs in general terms. We then focus the attention to EVs released by cells of the intestinal mucosa and their impact on intestinal homeostasis in health and disease. We specifically highlight their role on epithelial barrier integrity, wound healing of epithelial cells, immunity, and microbiota shaping. Microbiota-derived EVs are not reviewed here.

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Exercise training increases branched-chain oxoacid dehydrogenase kinase content in human skeletal muscle

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00115.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. R1335-R1341 ◽

Cited By ~ 18

Author(s):

Krista R. Howarth ◽

Kirsten A. Burgomaster ◽

Stuart M. Phillips ◽

Martin J. Gibala

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Protein Content ◽

Human Skeletal Muscle ◽

Acute Exercise ◽

Citrate Synthase ◽

Muscle Protein ◽

Moderate Intensity ◽

Main Effect ◽

Branched Chain

The branched-chain oxoacid dehydrogenase complex (BCOAD) is rate determining for the oxidation of branched-chain amino acids (BCAAs) in skeletal muscle. Exercise training blunts the acute exercise-induced activation of BCOAD (BCOADa) in human skeletal muscle (McKenzie S, Phillips SM, Carter SL, Lowther S, Gibala MJ, Tarnopolsky MA. Am J Physiol Endocrinol Metab 278: E580–E587, 2000); however, the mechanism is unknown. We hypothesized that training would increase the muscle protein content of BCOAD kinase, the enzyme responsible for inactivation of BCOAD by phosphorylation. Twenty subjects [23 ± 1 yr; peak oxygen uptake (V̇o2peak) = 41 ± 2 ml·kg−1·min−1] performed 6 wk of either high-intensity interval or continuous moderate-intensity training on a cycle ergometer ( n = 10/group). Before and after training, subjects performed 60 min of cycling at 65% of pretraining V̇o2peak, and needle biopsy samples (vastus lateralis) were obtained before and immediately after exercise. The effect of training was demonstrated by an increased V̇o2peak, increased citrate synthase maximal activity, and reduced muscle glycogenolysis during exercise, with no difference between groups (main effects, P < 0.05). BCOADa was lower after training (main effect, P < 0.05), and this was associated with a ∼30% increase in BCOAD kinase protein content (main effect, P < 0.05). We conclude that the increased protein content of BCOAD kinase may be involved in the mechanism for reduced BCOADa after exercise training in human skeletal muscle. These data also highlight differences in models used to study the regulation of skeletal muscle BCAA metabolism, since exercise training was previously reported to increase BCOADa during exercise and decrease BCOAD kinase content in rats (Fujii H, Shimomura Y, Murakami T, Nakai N, Sato T, Suzuki M, Harris RA. Biochem Mol Biol Int 44: 1211–1216, 1998).

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Skeletal muscle adaptations to exercise are not influenced by metformin treatment in humans: secondary analyses of two randomised, clinical trials.

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2021-0194 ◽

2021 ◽

Author(s):

Nanna Skytt Pilmark ◽

Laura Oberholzer ◽

Jens Frey Halling ◽

Jonas M. Kristensen ◽

Christina Pedersen Bønding ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Exercise Training ◽

Human Skeletal Muscle ◽

Acute Exercise ◽

Metformin Treatment ◽

Ampk Activation ◽

Double Blind ◽

Parallel Group ◽

Exercise Induced

Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise +/- metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed. Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g. the gut. Trial registration: ClinicalTrials.gov (NCT03316690 and NCT02951260). Novelty bullets • Metformin does not affect exercise-induced alterations in mitochondrial respiratory capacity in human skeletal muscle • Metformin does not affect exercise-induced alterations in systemic levels of oxidative stress nor emission of reactive oxygen species from human skeletal muscle • Metformin does not affect exercise-induced AMPK activation in human skeletal muscle

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