The role of extracellular vesicles in skeletal muscle and systematic adaptation to exercise
Open accessAbstract
Regular exercise has a central role in human health by reducing the risk of type 2 diabetes, obesity, stroke and cancer. How exercise is able to promote such systemic benefits has remained somewhat of a mystery but has been thought to be in part mediated by the release of myokines, skeletal muscle‐specific cytokines, in response to exercise. Recent studies have revealed skeletal muscle can also release extracellular vesicles (EVs) into circulation following a bout of exercise. EVs are small membrane‐bound vesicles capable of delivering biomolecules to recipient cells and subsequently altering their metabolism. The notion that EVs may have a role in both skeletal muscle and systemic adaptation to exercise has generated a great deal of excitement within a number of different fields including exercise physiology, neuroscience and metabolism. The purpose of this review is to provide an introduction to EV biology and what is currently known about skeletal muscle EVs and their potential role in the response of muscle and other tissues to exercise. image
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Written from the paper’s full text.
TL;DR
This review argues that extracellular vesicles (EVs) are emerging mediators of skeletal muscle intercellular communication and may help explain systemic adaptation to exercise alongside myokines. It summarizes EV biology, isolation challenges, and evidence that exercise alters EV cargo and miRNAs, while emphasizing that the field still lacks methods to isolate and track pure skeletal muscle-derived EVs.
Key findings
- Skeletal muscle can release EVs, and presumptive muscle-derived EVs have been identified by α-sarcoglycan and miR-206; α-sarcoglycan-positive EVs represented approximately 2–5% of the total EV population, and up to 5% of systemic EVs were positive for α-sarcoglycan.
- Exercise increases systemic EVs and alters EV cargo: 1 h of cycling increased systemic EVs taken up by the liver; exhaustive endurance exercise increased EV concentration; and endurance exercise changed the abundance of 322 serum proteins, with enrichment of proteins annotated to glycolysis.
- EV cargo can be selectively loaded and functional: myotube-derived EVs transfer cargo to myoblasts and regulate differentiation; dexamethasone-induced atrophy decreased myotube miR-23a but increased EV miR-23a, de-repressing atrogin-1 and MuRF-1; myogenic progenitor EVs taken up by fibroblasts down-regulate Rrbp1 via miR-206, regulating extracellular matrix remodelling.
- Exercise mode and intensity affect EV/myomiR release: acute endurance exercise increased EV miR-181a-5p but not miR-1, miR-133b, miR-206, miR-499 or miR-146a; in rats, downhill running increased serum EV miR-1, miR-133a/b, miR-206, miR-208a and miR-499, while uphill running did not conserve these results. The authors’ prediction analysis of 36 exercise-associated EV miRNAs yielded 5,486 possible targets, with the top enriched biological processes being response to reactive oxygen species and insulin secretion.
Methods
- Narrative review of EV biology, biogenesis, cellular uptake, isolation methods, and the emerging literature on skeletal muscle EVs and exercise adaptation.
- The authors compiled previously published plasma EV miRNAs after exercise (Table 1) and ran a target prediction analysis; this identified 36 miRNAs and 5,486 possible targets, followed by gene ontology enrichment.
- No primary experimental sample or new wet-lab dataset is described; the review synthesizes in vitro, rodent, and human studies.
Limitations
- Stated in the paper: current EV isolation methods cannot isolate pure populations of each EV subtype, especially when a single method is used; most biological findings regarding cell–cell communication may not be induced by exosomes alone.
- Stated in the paper: a major challenge is the inability to specifically label and track EVs released from skeletal muscle in vivo; the Whitham et al. isolation method for human plasma EVs would be expected to yield exosomes as well as microvesicles and apoptotic bodies.
- Evident from the text: as a review, it presents no new experimental data, and the authors’ prediction analysis is broad and focused on miRNA cargo rather than other EV cargo; several cited exercise studies examined plasma miRNAs without specifically isolating EVs.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 66 cited sources checked · 0 supported · 0 flagged
- Findingown data
The authors' prediction analysis identified 5486 possible targets of the 36 miRNAs found in EVs.
“Our prediction analysis totaled 5486 possible targets of the 36 miRNAs identified in EVs.”
Quote in the paperSubstantial claim - Interpretationreasoning
Most biological findings on cell-cell communication may not be caused by exosomes alone.
“Given this limitation, it is important to keep in mind that most of the biological findings regarding cell-cell communication may not necessarily be induced by exosomes alone.”
Quote in the paperNot a substantial claim - Premisecitation
Endocytic pathways including clathrin-mediated endocytosis, caveolin-dependent endocytosis, macropinocytosis, and phagocytosis participate in cellular uptake of EVs.
“All of these endocytic pathways have been shown to participate in the cellular uptake of EVs (Svensson et al. 2013; Tian et al. 2014); however, there is currently no data on whether one of these mechanisms is preferentially used for the uptake of skeletal muscle-derived EVs.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Svensson et al. 2013
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- cites Tian et al. 2014
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- Study design and conductcitation
Current EV isolation methods cannot isolate pure populations of each EV subtype, especially when only a single method is used.
“It is also important to note that the current methods used to isolate EVs are not capable of isolating pure populations of each EV subtype, especially if only a single method is used (Kowal et al. 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kowal et al. 2016
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- Premisecitation
Skeletal muscle can release extracellular vesicles into circulation after a bout of exercise.
“Recent studies have revealed skeletal muscle can also release extracellular vesicles (EVs) into circulation following a bout of exercise.”
- Also stated in: § Skeletal muscle as an endocrine organ · plain
“Guescini and co-workers were the first to describe exercise-induced release of EVs from skeletal muscle (Guescini et al. 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Guescini et al. 2015
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- Also stated in: § Skeletal muscle as an endocrine organ · plain
- Premisecitation
The mechanisms by which exercise produces changes across different tissues and organs remain poorly understood.
“How exercise is able to bring about such remarkable changes in different tissues and organs of the body remains poorly understood (Neufer et al. 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Neufer et al. 2015
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- Premisecitation
Release of myokines from contracting skeletal muscle is one proposed mechanism for the systemic benefits of regular exercise.
“One mechanism thought to mediate the systemic benefits of regular exercise is through the release of cytokines from contracting skeletal muscle known as myokines (Neufer et al. 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Neufer et al. 2015
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- Premisecitation
Exosomes can also bud directly from the plasma membrane.
“While the majority of studies have focused on the molecular mechanism involved in the endosomal biogenesis pathway, there is evidence suggesting that exosomes can also bud directly from the plasma membrane (Anderson et al. 2005; Booth et al. 2006; Fang et al. 2007; Shen et al. 2011; Bianchi et al. 2014; Nager et al. 2017).”
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- cites Booth et al. 2006
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- cites Fang et al. 2007
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- Premisereasoning
EVs mediate cell-cell communication by transferring functional cargo to recipient cells.
“Regardless of the current discussion about subtypes, EVs have been shown to mediate cell-cell communication through the transfer of functional cargo to recipient cells, expanding our understanding of how skeletal muscle (and other tissues) communicates to other organs.”
Quote in the paperSubstantial claim - Premisecitation
Skeletal muscle can function as an endocrine organ through EVs.
“The modalities through which skeletal muscle can function as an endocrine organ has expanded to include EVs (Rome et al. 2019; Trovato et al. 2019).”
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- cites Trovato et al. 2019
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- Premisecitation
Skeletal muscle can function as an endocrine organ.
“Over the last few decades, evidence has emerged that skeletal muscle can also function as an endocrine organ (Pedersen & Febbraio, 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Pedersen & Febbraio, 2012
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- Study design and conductcitation
The EV isolation method used by Whitham et al. (2 × 1 h centrifugation at 20,000 g) would be expected to yield exosomes as well as microvesicles and apoptotic bodies.
“Based on previous studies characterizing exosomes, employing the method (2 × 1 h centrifugation at 20,000 g) described by Whitham and coworkers for human plasma EV isolation would be expected to yield exosomes as well as other vesicles such as microvesicles and apoptotic bodies (Kowal et al. 2016; Jeppesen et al. 2019).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Kowal et al. 2016
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- cites Jeppesen et al. 2019
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- Premisecitation
Cargo contained within myotube-derived EVs can be transferred to myoblasts and regulate gene expression involved in myoblast differentiation.
“Furthermore, they also showed that the cargo contained within myotube-derived EVs could be transferred to myoblasts and subsequently regulate gene expression involved in myoblast differentiation (Forterre et al. 2014a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Forterre et al. 2014a
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- Rests on an assumption: Findings from in vitro myoblast and myotube EV studies can be extrapolated to skeletal muscle EV biology in vivo.
- Premisecitation
In rats, downhill running immediately increases serum EV levels of miR-1, miR-133a/b, miR-206, miR-208a and miR-499.
“Most recently, Yin and co-workers demonstrated that in response to downhill running miR-1, miR-133a/b, miR-206, miR-208a and miR-499 all significantly increased in serum EVs immediately after exercise in rats (Yin et al. 2019).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yin et al. 2019
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- Interpretationreasoning
Exercise mode and intensity are likely important factors to consider when investigating EV release into circulation.
“It should be noted that these studies did not specifically isolate EVs, rather they looked at miRNAs in the plasma; however, these results indicate that exercise mode and intensity are likely to be important factors to consider when investigating the release of EVs into circulation.”
Quote in the paperSubstantial claim - Interpretationown data
The authors' analysis provides a broad indication of possible systemic effects of exercise-induced EVs, particularly those carrying miRNAs.
“The data from our analysis provide a somewhat broad idea of the possible systemic effects of exercise-induced EVs, specifically in relation to EVs carrying miRNAs.”
Quote in the paperSubstantial claim- Rests on an assumption: The miRNAs previously reported in plasma EVs after exercise are representative of exercise-induced EV cargo relevant to systemic effects.
- Rests on an assumption: Predicted targets of EV miRNAs and their gene ontology enrichment reflect functional biological processes affected by exercise-induced EVs.
- Rests on an assumption: The plasma EVs analyzed in the cited studies are exercise-induced and relevant to skeletal muscle.
- Interpretationreasoning
The release of EVs may be fibre-type or muscle dependent, due to specific roles of EVs and their cargo in variability of skeletal muscle adaptation to exercise.
“These results suggest the release of EVs could be fibre-type or muscle dependent, owing to specific roles of EVs and their cargo in the variability of adaptation of skeletal muscle in response to exercise.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yin et al. 2019
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- Premisecitation
Exercise-induced changes in myomiRs vary among different skeletal muscles.
“Furthermore, the myomiR changes after exercise are not uniform across different skeletal muscles.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yin et al. 2019
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- Interpretationreasoning
Specific skeletal muscle adaptations to exercise may depend on the muscle fibre's ability to release or take up functional EV cargo.
“Therefore, specific skeletal muscle adaptations to exercise may rely on the muscle fibre’s ability to release or uptake EV functional cargo.”
Quote in the paperSubstantial claim - Premisecitation
The kinetics of EV release into circulation correlate with increased workload.
“This finding was consistent with an earlier study showing that the kinetics of EV release into circulation correlated with the increase in workload (Fruhbeis et al. 2015), suggesting a sufficient exercise intensity was required to detect a significant increase in EVs within systemic circulation.”
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- Premisecitation
The serum EV myomiR response to downhill running is not conserved after uphill running.
“Interestingly, these results were not conserved after a bout of uphill running”
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- Premisecitation
Different modalities of exercise affect the release of muscle-specific miRNAs.
“This concept was supported by another study that found different modalities of exercise were able to affect the release of muscle-specific miRNAs (Uhlemann et al. 2014).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Uhlemann et al. 2014
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- Premisecitation
Rrbp1 is a master regulator of collagen production.
“Rrbp1 is known to be a master regulator of collagen production.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fry et al. 2017
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- Premisecitation
Downhill running significantly changes miR-1 in both quadriceps and gastrocnemius muscles.
“The downhill protocol triggered significant fluctuations of miR-1 in both the quadriceps and gastrocnemius muscles.”
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- Premisecitation
Uphill running significantly changes miR-1 and miR-499 in the gastrocnemius only.
“In addition, the uphill running protocol prompted significant changes in the amount of miR-1 and miR-499 in the gastrocnemius only.”
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- Premisecitation
A bout of endurance exercise significantly changes the abundance of 322 serum proteins between rest and after exercise.
“They found a significant change in the abundance of 322 proteins between rest and following exercise.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Whitham et al. 2018
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- Premisecitation
In skeletal muscle hypertrophy, activated satellite cells are necessary for correct remodelling of the extracellular environment.
“The study by Fry and coworkers showed activated satellite cells were required for the proper remodelling of the extracellular environment during skeletal muscle hypertrophy (Fry et al. 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fry et al. 2017
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- Interpretationcitation
Whitham and colleagues demonstrated possible cross-talk between skeletal muscle and liver during acute exercise.
“While Whitham and colleagues demonstrated an exciting possible cross-talk between skeletal muscle and liver during acute exercise, the method used to isolate EVs should be taken into consideration when interpreting the results.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Whitham et al. 2018
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- Study design and conductreasoning
Studies on exercise-induced plasma miRNAs did not specifically isolate EVs.
“It should be noted that these studies did not specifically isolate EVs, rather they looked at miRNAs in the plasma; however, these results indicate that exercise mode and intensity are likely to be important factors to consider when investigating the release of EVs into circulation.”
Quote in the paperSubstantial claim - Premisecitation
miR-1 levels do not change in soleus or cardiac tissue after either downhill or uphill running.
“However, miR-1 levels did not change in the soleus or cardiac tissue in response to either downhill or uphill running.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yin et al. 2019
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- Premisecitation
Most current EV isolation methods cannot recover a single EV population because they rely on a single characteristic such as size or buoyant density.
“Most of the current methods for EV isolation are not capable of recovering a single EV population, mainly because the majority of isolation methods used are based on a single characteristic (e.g. size, buoyant density).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Van Deun et al. 2014
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- cites Kowal et al. 2016
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This EV-mediated mechanism properly regulates extracellular matrix remodelling.
“Through this mechanism, the remodelling of the extracellular matrix was properly regulated”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fry et al. 2017
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- Interpretationcitation
EV-mediated secretion of myomiRs into circulation depends on exercise mode.
“suggesting that the EV-mediated secretion of myomiRs (muscle-specific microRNAs) into circulation are exercise-mode dependent.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yin et al. 2019
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- Premisecitation
Gene ontology analysis of exercise-changed serum proteins shows enrichment of proteins with the keyword glycolysis.
“Gene ontology analysis revealed enrichment of proteins with the keyword ‘glycolysis’, consistent with previous work showing that EVs can deliver glycolytic enzymes to recipient cells and alter their glycolytic rate (Garcia et al. 2016; Zhao et al. 2016; Whitham et al. 2018).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Garcia et al. 2016
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- cites Zhao et al. 2016
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- cites Whitham et al. 2018
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- Premisecitation
Exercise can improve pancreatic β-cell function.
“studies have shown that exercise can improve pancreatic β-cell function (Dela et al. 2004; Malin et al. 2013)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Dela et al. 2004
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- cites Malin et al. 2013
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- Interpretationreasoning
These examples suggest a possible link between exercise-induced EVs and established systemic adaptations.
“These two examples provide a possible link between exercise-induced EVs and some of the systemic adaptions that have been established.”
Quote in the paperSubstantial claim- Rests on an assumption: The miRNAs previously reported in plasma EVs after exercise are representative of exercise-induced EV cargo relevant to systemic effects.
- Rests on an assumption: Predicted targets of EV miRNAs and their gene ontology enrichment reflect functional biological processes affected by exercise-induced EVs.
- Rests on an assumption: The plasma EVs analyzed in the cited studies are exercise-induced and relevant to skeletal muscle.
- May combine two claims. 18
- Classified as probably not a substantial claim. 7
May combine two claims.
PremisecitationMVBs can form without all four ESCRT components, revealing an ESCRT-independent pathway for exosome biogenesis.
“Somewhat surprising was the demonstration that MVBs are still capable of forming in the absence of all four ESCRT components (Stuffers et al. 2009), thus revealing an ESCRT-independent pathway for exosome biogenesis.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Stuffers et al. 2009
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PremisecitationRegular exercise lowers the risk of type 2 diabetes, obesity, stroke, and some cancers.
“Regular exercise is known to improve health by reducing the risk of type 2 diabetes, obesity, stroke and some forms of cancer (Garber et al. 2011).”
- Also stated in: § Abstract · plain
“Regular exercise has a central role in human health by reducing the risk of type 2 diabetes, obesity, stroke and cancer.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Garber et al. 2011
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- Also stated in: § Abstract · plain
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PremisecitationExosome biogenesis primarily occurs by inward invagination of late endosomes or multivesicular bodies to form intraluminal vesicles, which are released after fusion with the plasma membrane.
“The primary mechanism thought to be involved in exosome biogenesis is the inward invagination of late endosome/multivesicular bodies (MVBs) which give rise to intraluminal vesicles (ILVs); upon fusion with the plasma membrane, ILVs are released into the extracellular space as exosomes.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites de Gassart et al. 2004
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- cites Colombo et al. 2013
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PremisecitationEVs are membrane-bound vesicles that can transfer functional biomolecules such as lipids, proteins, nucleic acids, and sugars to recipient cells and alter their function.
“EVs are membrane-bound vesicles with the capacity to transfer functional biomolecules such as lipids, proteins, nucleic acids and sugars, thereby altering recipient cell function (Ratajczak et al. 2006; Valadi et al. 2007; Skog et al. 2008).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Ratajczak et al. 2006
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- cites Valadi et al. 2007
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- cites Skog et al. 2008
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PremisecitationMyokines can act in an autocrine, paracrine, or endocrine manner.
“Specifically, skeletal muscle has been shown to release cytokines, referred to as myokines, and/or exerkines (Pedersen et al. 2003; Pedersen & Febbraio, 2012; Whitham & Febbraio, 2016), which can act in an autocrine (e.g. interleukin-6, IL-6), paracrine (e.g. myostatin) or endocrine manner.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Pedersen et al. 2003
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- cites Pedersen & Febbraio, 2012
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- cites Whitham & Febbraio, 2016
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PremisecitationEVs can deliver glycolytic enzymes to recipient cells and alter their glycolytic rate.
“Gene ontology analysis revealed enrichment of proteins with the keyword ‘glycolysis’, consistent with previous work showing that EVs can deliver glycolytic enzymes to recipient cells and alter their glycolytic rate (Garcia et al. 2016; Zhao et al. 2016; Whitham et al. 2018).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Garcia et al. 2016
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- cites Zhao et al. 2016
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- cites Whitham et al. 2018
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PremisecitationUp to 5% of systemic EVs are positive for α-sarcoglycan and contain high levels of miR-206, confirming that these EVs are derived from skeletal muscle.
“A promising approach for isolating skeletal muscle-specific EVs was described by Guescini and colleagues, who showed that up to 5% of systemic EVs were positive for the muscle-enriched a-sarcoglycan protein and contained high levels of the skeletal muscle-specific microRNA, miR-206 – further confirmation that the α-sarcoglycan enriched EVs were derived from skeletal muscle (Guescini et al. 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Guescini et al. 2015
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InterpretationcitationmiR-23a is selectively exported from myotubes by EVs, leading to de-repression of atrogin-1 and MuRF-1, which promote muscle atrophy.
“This finding demonstrated that miR-23a was being selectively exported from myotubes by EVs, which in turn led to the de-repression of atrogin-1 and MuRF-1, target genes of miR-23a known to promote muscle atrophy.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe pathways of response to reactive oxygen species and insulin secretion have been previously discussed in relation to exercise.
“These pathways have been previously discussed in their response to exercise (He et al. 2016; Barlow & Solomon, 2018).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites He et al. 2016
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- cites Barlow & Solomon, 2018
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InterpretationcitationExercise is a strong stimulus for EV release into circulation, and exercise intensity influences how many EVs are released by skeletal muscle.
“Thus, exercise serves as a strong stimulus for promoting the release of EVs into circulation, with the intensity of exercise influencing how many EVs are presumably released by skeletal muscle.”
Quote in the paperSubstantial claim- Rests on an assumption: Exercise-induced increases in circulating EVs reflect EVs released by skeletal muscle.
May combine two claims.
PremisecitationConditional depletion of satellite cells disables this regulatory mechanism, causing muscle fibrosis from collagen over-production.
“however, when satellite cells were conditionally depleted, this regulatory mechanism was not operative, which caused fibrosis within the muscle as a result of collagen over-production.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fry et al. 2017
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PremisereasoningThe field of skeletal muscle extracellular vesicles is at an early stage, with few studies examining exercise effects on EV release from muscle, their cargo, and their uptake after exercise.
“As the preceding discussion highlights, the skeletal muscle EV field is still in its infancy, with only a handful of studies investigating how exercise affects the presumptive release of EVs from skeletal muscle, the identification of their protein and/or RNA cargo and what cells take up EVs following exercise.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationSubsequent studies confirmed an increase in serum EV abundance in response to exercise and the presence of EV miRNAs.
“Subsequent studies confirmed the increase in serum EV abundance in response to exercise and the presence of EV miRNAs (Fry et al. 2017; Lovett et al. 2018; Oliveira et al. 2018; D’Souza et al. 2018a).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Fry et al. 2017
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- cites Lovett et al. 2018
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- cites Oliveira et al. 2018
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PremisecitationmiRNA content in EVs correlates with exercise intensity, suggesting that intensity may affect EV packaging and release.
“Oliveira and colleagues observed a correlation between miRNA content in EVs and exercise intensity, proposing that intensity may play a role in the packaging and release of EVs (Oliveira et al. 2018).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Oliveira et al. 2018
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PremisecitationBoth myoblasts and myotubes are capable of releasing EVs.
“Despite the aforementioned challenges to studying skeletal muscle-derived EVs in vivo, numerous in vitro studies have clearly demonstrated that both myoblasts and myotubes (Le Bihan et al. 2012; Romancino et al. 2013; Forterre et al. 2014a,b; Choi et al. 2016) are capable of releasing EVs.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Le Bihan et al. 2012
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- cites Romancino et al. 2013
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- cites Forterre et al. 2014a,b
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- Rests on an assumption: Findings from in vitro myoblast and myotube EV studies can be extrapolated to skeletal muscle EV biology in vivo.
May combine two claims.
PremisecitationAfter an acute bout of endurance exercise, EV miR-181a-5p increases significantly, while EV miR-1, miR-133b, miR-206, miR-499, and miR-146a do not change.
“These authors found that after an acute bout of endurance exercise there was a significant increase in the abundance of EV miR-181a-5p but no change in the abundance of miR-1, miR-133b, miR-206, miR-499 or miR-146a within EVs (Guescini et al. 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Guescini et al. 2015
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PremisecitationDexamethasone-induced myotube atrophy causes a significant decrease in myotube miR-23a expression and a parallel increase in EV miR-23a abundance.
“A nice example of the selective loading of EVs was the study by Hudson and co-workers showing dexamethasone-induced myotube atrophy caused a significant decrease in myotube miR-23a expression that was paralleled by an increase in the abundance of EV miR-23a (Hudson et al. 2014).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hudson et al. 2014
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PremisecitationSystemic EV concentration is higher immediately after a single bout of exhaustive endurance exercise, with EV size and composition changing during early recovery while abundance remains elevated.
“Additionally, Frtihbeis and colleagues reported systemic EV concentration was higher immediately following a single bout of exhaustive endurance exercise, with EV size and composition differing during the early recovery phase despite EV abundance remaining elevated (Fruhbeis et al. 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fruhbeis et al. 2015
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InterpretationreasoningEV loading does not necessarily reflect the intracellular composition of the cell and appears to be regulated by a yet-to-be-described mechanism.
“This early work revealed that the loading of EVs does not necessarily reflect the intracellular composition of the cell but appears to be regulated by a yet-to-be described mechanism.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationMyogenic progenitor cells release EVs that fibroblasts take up, which down-regulates Rrbp1 through muscle-specific miR-206.
“In particular, myogenic progenitor cells were shown to release EVs which were taken up by fibroblasts, leading to down-regulation of Rrbp1 via muscle-specific miR-206”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fry et al. 2017
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Classified as probably not a substantial claim.
InterpretationreasoningEV-mediated intercellular communication might be a new mechanism by which exercise produces systemic benefits.
“That such intercellular communication could provide a novel mechanism for how exercise promotes systemic benefits has generated a deal of interest in the exercise physiology field, as well as other fields such neuroscience, metabolism and cancer.”
Quote in the paperSubstantial claim- Rests on an assumption: EVs can deliver cargo to recipient cells and alter their metabolism.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenThe benefits of exercise-induced EVs could be mediated by cargo other than miRNAs.
“While our analysis focused on the miRNA within EVs, the benefits of exercise-induced EVs could be mediated by other types of cargo.”
Quote in the paperNot a substantial claim- Rests on an assumption: The miRNAs previously reported in plasma EVs after exercise are representative of exercise-induced EV cargo relevant to systemic effects.
- Rests on an assumption: Predicted targets of EV miRNAs and their gene ontology enrichment reflect functional biological processes affected by exercise-induced EVs.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationExercise can increase antioxidant enzymatic activity.
“and increase antioxidant enzymatic activity (Berzosa et al. 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Berzosa et al. 2011
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The paper relies on this without support.
Findings from in vitro myoblast and myotube EV studies can be extrapolated to skeletal muscle EV biology in vivo.
“Despite the aforementioned challenges to studying skeletal muscle-derived EVs in vivo, numerous in vitro studies have clearly demonstrated that both myoblasts and myotubes (Le Bihan et al. 2012; Romancino et al. 2013; Forterre et al. 2014a,b; Choi et al. 2016) are capable of releasing EVs.”
The paper relies on this without support.
Exercise-induced increases in circulating EVs reflect EVs released by skeletal muscle.
“Thus, exercise serves as a strong stimulus for promoting the release of EVs into circulation, with the intensity of exercise influencing how many EVs are presumably released by skeletal muscle.”
The paper relies on this without support.
The miRNAs previously reported in plasma EVs after exercise are representative of exercise-induced EV cargo relevant to systemic effects.
“we compiled a list of previously published miRNAs that were isolated from plasma EVs after a bout of exercise”
“The data from our analysis provide a somewhat broad idea of the possible systemic effects of exercise-induced EVs”
The paper relies on this without support.
Predicted targets of EV miRNAs and their gene ontology enrichment reflect functional biological processes affected by exercise-induced EVs.
“We then ran a prediction analysis to determine possible targets of EV carrying miRNAs”
The paper relies on this without support.
The plasma EVs analyzed in the cited studies are exercise-induced and relevant to skeletal muscle.
“previously published miRNAs that were isolated from plasma EVs after a bout of exercise”
“possible systemic effects of exercise-induced EVs”
The paper relies on this without support.
EVs can deliver cargo to recipient cells and alter their metabolism.
“The discovery that EVs are capable of delivering their cargo to a recipient cell and altering its metabolism”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Exerkines include a broad range of signalling moieties such as cytokines, nucleic acids, lipids and metabolites, often carried by cell-specific extracellular vesicles.
“Exerkines are increasingly recognized to include a broad range of signalling moieties, including cytokines, nucleic acids (microRNA17, mRNA and mitochondrial DNA), lipids and metabolites, which are frequently driven by cell-specific extracellular vesicle secretion18.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [18]
Extracellular vesicles are membranous structures released from almost all cell types with cell-specific profiles, ranging in size from 150 to 1,000 nm and carrying proteins, nucleic acids and lipids.
“Extracellular vesicles are membranous structures that are released from almost all cell types, with cell-specific profiles. They vary in size, ranging from 150 nm to 1,000 nm, and carry an assortment of material, including proteins, nucleic acids and lipids18,34.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [18]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Wenzel citation year does not match the reference list
MinorThe text cites Wenzel et al. as a 2016 publication, but the only Wenzel entry in the reference list is dated 2018.
“Kalra et al. 2016; Wenzel et al. 2016).”
“122. Wenzel EM, Schultz SW, Schink KO, Pedersen NM, Nahse V, Carlson A, Brech A, Stenmark H & Raiborg C (2018).”
The citation lists haven’t been fetched yet
References 133 · Cited by 141
Research works printed but not linked: 1
- 10.1152/ajpendo.00138.2018 · DOI
- Authors
- Vechetti, I. J., Valentino, T., Mobley, C. B., & McCarthy, J. J.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- McCarthy, John J.
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2020-02-18
- Volume
- 599
- Issue
- 3
- Pages
- 845-861
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC7363579
- OpenAlex
- W2999852770
- Semantic Scholar
- 76ebe197601a4ef71c1904b4bdc5edd484e6adb0
- Cited by
- 141
- References
- 133
- Citations by year
- 2026: 29 · 2025: 14 · 2024: 24 · 2023: 27 · 2022: 30 · 2021: 12 · 2020: 5
- FWCI
- 1.77
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK119619)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- extracellular vesicles, skeletal muscle, exercise adaptation, myokines, exercise physiology, intercellular communication
- MeSH terms
- Extracellular Vesicles, Adaptation, Physiological, Diabetes Mellitus, Type 2, Humans, Exercise, Muscle, Skeletal
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
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