The role of extracellular vesicles in skeletal muscle and systematic adaptation to exercise

Vechetti, Ivan J.; Valentino, Taylor; Mobley, C. Brooks; McCarthy, John J.

doi:10.1113/jp278929

Cited by 80 publications

(93 citation statements)

References 135 publications

(249 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Effectively blocking EV release in a cell type-specific fashion in vivo is complicated and presents a variety of technical challenges. 38 In order to search for candidate muscle fiber genes whose expression is potentially affected by satellite cell EVs during hypertrophy in vivo , we turned to our previously published murine model of inducible satellite cell depletion, the Pax7-Diptheria Toxin A (Pax7-DTA) model. 6 , 8 , 10 Specifically, using an unbiased approach, we aimed to identify genes that were similarly expressed between satellite cell replete and deplete muscle at rest, but were lower in the presence of satellite cells following MOV, which could indicate EV-mediated delivery of repressive microRNAs (miRNAs) to target cells by activated satellite cells.…”

Section: Resultsmentioning

confidence: 99%

Fusion-Independent Satellite Cell Communication to Muscle Fibers During Load-Induced Hypertrophy

et al. 2020

View full text Add to dashboard Cite

Abstract The “canonical” function of Pax7+ muscle stem cells (satellite cells) during hypertrophic growth of adult muscle fibers is myonuclear donation via fusion to support increased transcriptional output. In recent years, however, emerging evidence suggests that satellite cells play an important secretory role in promoting load-mediated growth. Utilizing genetically modified mouse models of delayed satellite cell fusion and in vivo extracellular vesicle tracking, we provide evidence for satellite cell communication to muscle fibers during hypertrophy. Myogenic progenitor cell extracellular vesicle-mediated communication to myotubes in vitro influences extracellular matrix (ECM)-related gene expression, which is congruent with in vivo overload experiments involving satellite cell depletion, as well as in silico analyses. Satellite cell-derived extracellular vesicles can transfer a Cre-induced, cytoplasmic-localized fluorescent reporter to muscle cells as well as miRNAs that regulate ECM genes such as matrix metalloproteinase 9 (Mmp9), which may facilitate growth. Delayed satellite cell fusion did not limit long-term load-induced muscle hypertrophy indicating that early fusion-independent communication from satellite cells to muscle fibers is an under-appreciated aspect of satellite cell biology. We cannot exclude the possibility that satellite cell-mediated myonuclear accretion is necessary to maintain prolonged growth, specifically in the later phases of adaptation, but these data collectively highlight how extracellular vesicle delivery from satellite cells can directly contribute to mechanical load-induced muscle fiber hypertrophy, independent of cell fusion to the fiber.

show abstract

Section: Resultsmentioning

confidence: 99%

Fusion-Independent Satellite Cell Communication to Muscle Fibers During Load-Induced Hypertrophy

et al. 2020

View full text Add to dashboard Cite

show abstract

“…More recently, the analysis of the methylation profile of cfDNA shows that about 32% of cfDNA is derived from granulocytes, 30% from erythrocyte progenitors, 23% from monocytes and lymphocytes, 9% from endothelial cells, and only 6% from other cells including neurons and hepatocytes [ 11 ], while a sub-characterization for exercise released cfDNA has not been conducted yet. We and others found that next to muscle cells, platelets, endothelial cells, and leukocytes, significantly contribute to the pool of EVs released into plasma following physical exercise (reviewed in [ 47 , 62 , 63 , 64 ]). Like for cfDNA, the underlying signaling mechanisms are not fully understood, but an association with shear stress and the activation of coagulative processes are discussed [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Kinetics and Topology of DNA Associated with Circulating Extracellular Vesicles Released during Exercise

Neuberger

Hillen

Mayr

et al. 2021

Genes

View full text Add to dashboard Cite

Although it is widely accepted that cancer-derived extracellular vesicles (EVs) carry DNA cargo, the association of cell-free circulating DNA (cfDNA) and EVs in plasma of healthy humans remains elusive. Using a physiological exercise model, where EVs and cfDNA are synchronously released, we aimed to characterize the kinetics and localization of DNA associated with EVs. EVs were separated from human plasma using size exclusion chromatography or immuno-affinity capture for CD9+, CD63+, and CD81+ EVs. DNA was quantified with an ultra-sensitive qPCR assay targeting repetitive LINE elements, with or without DNase digestion. This model shows that a minute part of circulating cell-free DNA is associated with EVs. During rest and following exercise, only 0.12% of the total cfDNA occurs in association with CD9+/CD63+/CD81+EVs. DNase digestion experiments indicate that the largest part of EV associated DNA is sensitive to DNase digestion and only ~20% are protected within the lumen of the separated EVs. A single bout of running or cycling exercise increases the levels of EVs, cfDNA, and EV-associated DNA. While EV surface DNA is increasing, DNAse-resistant DNA remains at resting levels, indicating that EVs released during exercise (ExerVs) do not contain DNA. Consequently, DNA is largely associated with the outer surface of circulating EVs. ExerVs recruit cfDNA to their corona, but do not carry DNA in their lumen.

show abstract

“…The heterogeneity of EV populations and other bioactive particles in blood faces EV research with numerous challenges and, thus, confuses the determination of EVs released into the circulation upon physical exercise (ExerVs). The modalities of ExerV-release, the putative role in adaptation signaling as well as prospective therapeutic and diagnostic applications were recently highlighted and comprehensively summarized (e.g., Trovato et al, 2019 ; Fuller et al, 2020 ; Vechetti et al, 2020 ). Here, we supplement this body of literature with a compilation of the most relevant technical limitations regarding ExerV isolation and characterization, focusing on sEVs.…”

Section: Introductionmentioning

confidence: 99%

Considerations for the Analysis of Small Extracellular Vesicles in Physical Exercise

et al. 2020

View full text Add to dashboard Cite

Physical exercise induces acute physiological changes leading to enhanced tissue cross-talk and a liberation of extracellular vesicles (EVs) into the circulation. EVs are cell-derived membranous entities which carry bioactive material, such as proteins and RNA species, and are important mediators of cell-cell-communication. Different types of physical exercise interventions trigger the release of diverse EV subpopulations, which are hypothesized to be involved in physiological adaptation processes leading to health benefits and longevity. Large EVs (“microvesicles” and “microparticles”) are studied frequently in the context of physical exercise using straight forward flow cytometry approaches. However, the analysis of small EVs (sEVs) including exosomes is hampered by the complex composition of blood, confounding the methodology of EV isolation and characterization. This mini review presents a concise overview of the current state of research on sEVs released upon physical exercise (ExerVs), highlighting the technical limits of ExerV analysis. The purity of EV preparations is highly influenced by the co-isolation of non-EV structures in the size range or density of EVs, such as lipoproteins and protein aggregates. Technical constraints associated with EV purification challenge the quantification of distinct ExerV populations, the identification of their cargo, and the investigation of their biological functions. Here, we offer recommendations for the isolation and characterization of ExerVs to minimize the effects of these drawbacks. Technological advances in the ExerV research field will improve understanding of the inter-cellular cross-talk induced by physical exercise leading to health benefits.

show abstract

The role of extracellular vesicles in skeletal muscle and systematic adaptation to exercise

Cited by 80 publications

References 135 publications

Fusion-Independent Satellite Cell Communication to Muscle Fibers During Load-Induced Hypertrophy

Fusion-Independent Satellite Cell Communication to Muscle Fibers During Load-Induced Hypertrophy

Kinetics and Topology of DNA Associated with Circulating Extracellular Vesicles Released during Exercise

Considerations for the Analysis of Small Extracellular Vesicles in Physical Exercise

Contact Info

Product

Resources

About