Estrogenic Regulation of Exercise Response - Role of Extracellular Vesicles and HDL as Signal Carriers (ErROR)


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Funds granted by main funder (€)

286 601,00


Funding program

Postdoctoral Researcher, AoF (Academy of Finland)


Project timetable

Project start date: 01/09/2020

Project end date: 31/08/2023


Summary

The major hormonal challenge that every aging women confronts is menopause. It leads to estradiol deficiency that has been linked to impairment of skeletal muscle function leading to increased adiposity accompanied with increased metabolic and cardiovascular disease risks. Due to difficulties in assessing the actions of a single hormone in in vivo models, the results from estradiol’s effects on acute exercise in the current literature are inconsistent. However, studies support that estradiol (E2) induces lipid utilization during exercise. Yet to date it is not known which route the effects of E2 are transmitted. Recent years the role of extracellular vesicles (EVs) as signaling molecule carriers have raised interest in the field of tissue crosstalk. EVs carry proteins, lipids and nucleic acids, such as microRNAs (miRs) that are key regulators of cell metabolism. So far, studies have established both E2 associated miRs and exercise responsive miRs, yet we lack the information whether E2 alters the exercise responsive miR-pool. My current study aims to establish E2 linked, systematically delivered miRs that may be responsible for the change seen in the exercise response after menopause. In my study, I will utilize unique muscle bath setup to establish whether E2 alters the miR signaling that originates from exercising muscle via EVs. Furthermore, by combining animal and human research I will explore whether E2 alters the miR pool in EVs or high-density lipoprotein (HDL) particles or both. Currently the standard protocol is to isolate EVs and HDL together, yet these carriers may have distinct function in cell signaling, and thus it is vital to begin to study the cargo of EVs and HDL separately. I will combine ultracentrifugation with size-exclusion chromatography (SEC) to yield pure, separate EV and HDL preparations. The microRNA-pool within the EVs and HDL will be explored using next-generation sequencing (NGS) and key findings will be verified using Q-PCR. Finally, if I succeed to find key miRs that are altered during acute exercise in E2 deficient state, I will examine whether those miRs alter target tissue metabolism. I expect the results of my study to be translational to human health in finding new therapeutic miRs that can help inhibiting excess fat accumulation and hence prevention of metabolic and cardiovascular diseases.


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Last updated on 2020-08-05 at 14:05