Exercise increases the release of NAMPT in extracellular vesicles and alters <scp>NAD</scp><sup>+</sup> activity in recipient cells

Extracellular vesicles (EVs) have been suggested to transmit the health-promoting effects of exercise throughout the body. Yet, the mechanisms by which beneficial information is transmitted from extracellular vesicles to recipient cells are poorly understood, precluding a holistic understanding of how exercise promotes cellular and tissue health. In this study, using articular cartilage as a model, we introduced a network medicine paradigm to simulate how exercise facilitates communication between circulating EVs and chondrocytes, the cells resident in articular cartilage. Using the archived small RNA-seq data of EV before and after aerobic exercise, microRNA regulatory network analysis based on network propagation inferred that circulating EVs activated by aerobic exercise perturb chondrocyte-matrix interactions and downstream cellular aging processes. Building on the mechanistic framework identified through computational analyses, follow up experimental studies interrogated the direct influence of exercise on EV-mediated chondrocyte-matrix interactions. We found that pathogenic matrix signaling in chondrocytes was abrogated in the presence of exercise-primed EVs, restoring a more youthful phenotype, as determined by chondrocyte morphological profiling and evaluation of chondrogenicity. Epigenetic reprograming of the gene encoding the longevity protein, α-Klotho, mediated these effects. These studies provide mechanistic evidence that exercise transduces rejuvenation signals to circulating EVs, endowing EVs with the capacity to ameliorate cellular health even in the presence of an unfavorable microenvironmental signals.

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“…3F). This is consistent with a previous study demonstrating that the uptake of circulating EVs by recipient C2C12 occurs within 60 minutes 43 .…”

Section: Exercise-primed Evs Overrode Chondrocyte Morphological Alter...supporting

confidence: 93%

Exercise-primed extracellular vesicles improve cell-matrix adhesion and chondrocyte health

Wang

D'Amico

Tang

et al. 2023

Preprint

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“…Twenty‐eight healthy men who were part of a larger study 17 were randomly selected from young, mature, and unfit and fit categories for additional proteomic investigation of sEVs, using an online random number generator available at https://randomchoicegenerator.com/. The inclusion criteria included aged between 18–35 and 50–70 years, healthy with no known clinical disease, and free from lower body injury 2 months prior to participation.…”

Section: Methodsmentioning

confidence: 99%

“…Twenty-eight healthy men who were part of a larger study 17 were randomly selected from young, mature, and unfit and fit categories for additional proteomic investigation of sEVs, using an online random number generator available at https:// rando mchoi cegen erator. com/ .…”

Section: Participantsmentioning

confidence: 99%

“…Participants were asked to attend two experimental trials on separate days, as previously described. 17 In brief, during the first trial, participants were asked to perform a YMCA submaximal cycle ergometer test to estimate their maximum oxygen consumption (VO 2peak ). The YMCA submaximal cycle ergometer test was conducted as described.…”

Section: Experimental Protocolmentioning

confidence: 99%

“…[8][9][10] The secretion of EVs has therefore been proposed as one of the important mechanisms of tissue crosstalk during exercise. [11][12][13][14] We and others have reported the release of sEVs into the circulation in healthy males after acute aerobic exercise [15][16][17] ; however, much of the attention has been put on the surface and size characterization of exercise EVs. To fully explore the functional effect of EVs on health, understanding the cargo of exercise sEVs is pivotal.…”

Section: Introductionmentioning

confidence: 99%

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Acute exercise‐induced release of innate immune proteins via small extracellular vesicles changes with aerobic fitness and age

Chong,

Shah,

Schittenhelm

et al. 2024

Acta Physiologica

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AimPhysical exercise triggers the secretion of small extracellular vesicles (sEVs) into the circulation in humans, enabling signalling crosstalk between tissues. Exercise‐derived EVs and their cargo have been proposed to mediate adaptations to exercise; however, our understanding of how exercise‐derived EV protein cargo is modulated by factors such as aerobic fitness and age of an individual is currently unknown. Here, we examined the circulating sEV proteome following aerobic exercise in healthy males of different ages and aerobic fitness to understand exercise‐induced EV response during the aging process.MethodsTwenty‐eight healthy men completed a bout of 20‐min cycling exercise at 70% estimated VO2peak. Small EVs were isolated from blood samples collected before and immediately after exercise, and then quantified using particle analysis and Western blotting. Small EV proteome was examined using quantitative proteomic analysis.ResultsWe identified a significant increase in 13 proteins in small plasma EVs following moderate‐to‐vigorous intensity exercise. We observed distinct changes in sEV proteome after exercise in young, mature, unfit, and fit individuals, highlighting the impact of aerobic fitness and age on sEV protein secretion. Functional enrichment and pathway analysis identified that the majority of the significantly altered sEV proteins are associated with the innate immune system, including proteins known to be damage‐associated molecular patterns (DAMPs).ConclusionTogether, our findings suggest that exercise‐evoked acute stress can positively challenge the innate immune system through the release of signalling molecules such as DAMPs in sEVs, proposing a novel EV‐based mechanism for moderate‐to‐vigorous intensity exercise in immune surveillance pathways.

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Targeting mitophagy for neurological disorders treatment: advances in drugs and non-drug approaches

Xiong

Zhang

Luo

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Exercise increases the release of NAMPT in extracellular vesicles and alters NAD⁺ activity in recipient cells

Cited by 28 publications

References 25 publications

Exercise-primed extracellular vesicles improve cell-matrix adhesion and chondrocyte health

Exercise-primed extracellular vesicles improve cell-matrix adhesion and chondrocyte health

Acute exercise‐induced release of innate immune proteins via small extracellular vesicles changes with aerobic fitness and age

Targeting mitophagy for neurological disorders treatment: advances in drugs and non-drug approaches

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Exercise increases the release of NAMPT in extracellular vesicles and alters NAD+ activity in recipient cells

Cited by 28 publications

References 25 publications

Exercise-primed extracellular vesicles improve cell-matrix adhesion and chondrocyte health

Exercise-primed extracellular vesicles improve cell-matrix adhesion and chondrocyte health

Acute exercise‐induced release of innate immune proteins via small extracellular vesicles changes with aerobic fitness and age

Targeting mitophagy for neurological disorders treatment: advances in drugs and non-drug approaches

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Product

Resources

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Exercise increases the release of NAMPT in extracellular vesicles and alters NAD⁺ activity in recipient cells