Utility of small extracellular vesicles in informing biological responses to exercise and ageing

Parker, Hannah-Jade ORCID: 0000-0001-7540-6337 (2024). Utility of small extracellular vesicles in informing biological responses to exercise and ageing. University of Birmingham. Ph.D.

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Abstract

Small extracellular vesicles (sEVs) are nano-sized particles containing proteins, metabolites, lipids, and RNA that can be transferred between cells. sEVs have been implicated in various biological processes. These include exercise, ageing, and cellular senescence. Understanding how sEVs are impacted by these processes may be informative of how these processes work. Additionally, due to the significant release of sEVs that has been reported as part of the senescence-associated secretory phenotype (SASP), and the relative clinical accessibility of circulating sEVs, it may be possible to identify candidate biomarkers of senescence. This thesis investigated the impact that exercise (both acute and chronic), ageing and senescence have on the sEV count and proteome, with an overarching aim to determine the utility of studying sEVs in these
wider contexts. Chapter 2 aimed to determine whether there were significant differences in circulating sEV number after a bout of high intensity cardio-based exercise. This was done by using single EV particle analysis to count circulating sEVs in response to high intensity interval
exercise. It was found that there was a statistically significant release of sEVs positive for the CD9, CD63, CD81 and CD41a tetraspanins. Chapter 3 aimed to further investigate the proteome of sEVs released found within sEVs released during senescence, and whether any of these could have been candidate biomarkers. Using three different methods of inducing senescence, we tested senescence-derived sEVs using nano ultra-high performance liquid chromatography-tandem mass spectrometry (nano UHPLC-MS/MS). Experimentally induced senescence effected a large change in the sEV proteome with NIT2, CARS, EEF1A2, GSTO1, PGAM 1, PGAM 2 and NAMPT identified as candidate biomarkers of senescence.
Finally, Chapter 4 aimed to identify whether there were any significant quantitative or proteomic differences in circulating sEVs in response to ageing or chronic exercise. This was achieved by examining the impact of ageing and chronic exercise on sEVs in vivo, via single EV
particle analysis on young plasma, older adult plasma, and Masters athlete plasma. Although there were significantly fewer CD9 positive sEVs in older adults than in the young cohort, and significantly less CD9 protein expression in Masters athletes compared to the young cohort, there was no large difference in number of circulating sEVs between cohort considering age or chronic exercise. In addition to no major differences in sEV count, nano UHPLC-MS/MS revealed only minor differences in the circulating sEV proteome, including no difference in the candidate markers of
senescence. These works indicate that although sEVs are released in response to acute exercise and senescence, there are limited differences in sEV count and protein cargo between young, old and Masters athletes implying a broad look at sEVs does not inform the ageing process nor the impact of lifelong exercise.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):