Extracellular vesicles and high-density lipoproteins: Exercise and estrogen-responsive small RNA carriers

Abstract

Decreased systemic estrogen levels (i.e., menopause) affect metabolic health. However, the detailed mechanisms underlying this process remain unclear. Both estrogens and exercise have been shown to improve metabolic health, which may be partly mediated by circulating microRNA (c-miR) signaling. In recent years, extracellular vesicles (EV) have increased interest in the field of tissue crosstalk. However, in many studies on EV-carried miRs, the co-isolation of high-density lipoprotein (HDL) particles with EVs has not been considered, potentially affecting the results. Here, we demonstrate that EV and HDL particles have distinct small RNA (sRNA) content, including both host and nonhost sRNAs. Exercise caused an acute increase in relative miR abundancy in EVs, whereas in HDL particles, it caused an increase in transfer RNA-derived sRNA. Furthermore, we demonstrate that estrogen deficiency caused by menopause blunts acute exercise-induced systemic miR-response in both EV and HDL particles.

Defining the influence of size‐exclusion chromatography fraction window and ultrafiltration column choice on extracellular vesicle recovery in a skeletal muscle model

“…Additional contamination factors, such as other lipids or metabolites, were not accounted for in our research. Currently, soluble proteins or miRNAs are the most studied contaminants alongside lipoproteins in in vitro (Böing et al., 2014; Coenen‐Stass et al., 2019; Pavani et al., 2020) and in vivo research (Karvinen et al., 2022; Kobayashi et al., 2021; Maggio et al., 2023). Future studies will be needed to better identify the extent of non‐lipoprotein contaminants in EV preparations, particularly for SM applications.…”

A Novel Pathway of Functional microRNA Uptake and Mitochondria Delivery

“…These studies have demonstrated that extracellular miRNAs enter mammalian cells through multiple mechanisms, such as exosome-mediated endocytosis, micropinocytosis or macropinocytosis, and the internalization process mediated by various RNA-binding proteins [16][17][18]21] and lipoproteins. [19][20][21]45] As small RNA phase separation mediated by serum cationic protein is not dependent upon exosomes or specific RNA binding proteins, it may serve as a general uptake pathway for various small RNAs, especially those not encapsulated in exosomes or associated with RNA-binding protein or lipoproteins.…”

“…Third, extracellular miRNAs can also be associated with highdensity lipoproteins (HDL) and low-density lipoproteins (LDL), two highly abundant miRNA carriers. [18][19][20] As one of the most critical miRNA carriers, these lipoproteins can mediate extracellular miRNA uptake in various cells. [18,21] For example, Vickers et al found that the profile of HDL-associated miRNAs was different from that in exosomes, and that HDL-mediated miR-223 uptake could repress cholesterol uptake by directly downregulating the scavenger receptor BI.…”