CIRCULATING EXTRACELLULAR VESICLES RELEASED AFTER ISCHEMIC EXERCISE EXHIBIT AN ALTERED MIRNA PROFILE AND INDUCE PROLIFERATION OF SKELETAL MUSCLE PRECURSOR CELLS

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Background
Transient sub-lethal ischemia (remote ischemic conditioning, RIC) can promote protective effect against cardiac muscle tissue degradation inherent of lethal ischemia. Protective effects of RIC may involve miRNA derived from extracellular vesicles (EVs) to affect gene expression in remote tissues. EVs are released in plasma after ischemic conditioning and traditional exercise. Ischemic exercise conducted as low-load blood flow restricted resistance exercise (BFRE) can precondition skeletal muscle and promote muscle accretion. This low intensity ischemic exercise regime may be more feasible for clinical populations where high mechanical loading and/or intensity exercise, is untenable. Muscle regenerative and growth processes are partly reliant on activation of muscle precursor cells. Extracellular miRNA elicited by BFRE may stimulate muscle precursor cells, to potentially exert effect on remote skeletal and cardiac tissue.
The aim of the study was to investigate the effect of low intensity BFRE on EV profile, miRNA cargo and skeletal muscle precursor cell proliferation.

Methods
EVs were isolated from plasma collected from 6 healthy human subjects before and 1 hour after a single bout of BFRE. During BFRE, a tourniquet cuff was wrapped around the proximal part of the thigh and inflated to a pressure of 100 mmHg by a digital tourniquet system with automatic regulation of cuff pressure. Exercise was conducted as five sets of knee extensions, with each set conducted to volitional failure with 30 % of 1 Repeat Maximum (RM), and with 45 seconds of recovery between sets. EVs were characterized by NTA, TRPS, western blotting and electron microscopy. Small EV RNAs were isolated and sequenced by NGS. Differential expression of EV miRNAs was analyzed by DESeq2 followed by functional enrichment analysis. Isolated EVs were applied in an in vitro proliferation assay on primary muscle stem cells and fatty acid progenitor cells, to test the ability BFRE primed EVs to stimulate proliferation.

Results
No difference in EV quantity or size was observed after BFRE. Expression of 12 miRNAs was significantly altered after BFRE. Target prediction and functional enrichment analysis of these miRNAs revealed several target genes and association to several biological pathways involved in skeletal muscle protein turnover. Interestingly, BFRE-conditioned EVs significantly increased the proliferation of muscle precursor cells.

Summary/Conclusion
The results support that BFRE promote EV-derived miRNA to engage in muscle remodeling and/or growth processes. Moreover, this suggest for a way for ischemia and/or exercise to exert protective effects in remote tissues.
Original languageEnglish
Publication year6 May 2019
Publication statusPublished - 6 May 2019
EventDanish Diabetes Academy: Non-coding RNA´s in Metabolic Disease - Copenhagen, Denmark
Duration: 6 May 20198 May 2019
https://www.rna-metabolism.com/

Conference

ConferenceDanish Diabetes Academy: Non-coding RNA´s in Metabolic Disease
CountryDenmark
CityCopenhagen
Period06/05/201908/05/2019
Internet address

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ID: 154382558