CIRCULATING EXTRACELLULAR VESICLES RELEASED AFTER ISCHEMIC EXERCISE EXHIBIT AN ALTERED MIRNA PROFILE AND INDUCE PROLIFERATION OF SKELETAL MUSCLE PRECURSOR CELLS
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".