Circulating inflammatory miRNA signature in response to different doses of aerobic exercise.

While moderate acute exercise has been associated with strong anti-inflammatory mechanisms, strenuous exercise has been linked to deleterious inflammatory perturbations. It is therefore fundamental to elucidate the mechanisms that regulate the exercise-induced inflammatory cascade. Information on novel regulators such as circulating inflammatory microRNAs (c-inflammamiRs) is incomplete. In this study, we evaluated the response of a panel of c-inflammamiRs to different doses of acute aerobic exercise. We first studied the exercise-induced inflammatory cascade in serum samples of nine active middle-aged males immediately before and after (0 h, 24 h, 72 h) 10-km, half-marathon, and marathon races. Next, we analyzed the circulating profile of 106 specific c-inflammamiRs immediately before) and after (0 h, 24 h) 10-km (low inflammatory response) and marathon (high inflammatory response) races. Analysis of classical inflammatory parameters revealed a dose-dependent effect of aerobic exercise on systemic inflammation, with higher levels detected after marathon. We observed an increase in miR-150-5p immediately after the 10-km race. Levels of 12 c-inflammamiRs were increased immediately after the marathon (let-7d-3p, let-7f-2-3p, miR-125b-5p, miR-132-3p, miR-143-3p, miR-148a-3p, miR-223-3p, miR-223-5p, miR-29a-3p, miR-34a-5p, miR-424-3p, and miR-424-5p). c-inflammamiRs returned to basal levels after 24 h. Correlation and in silico analyses supported a close association between the observed c-inflammamiR pattern and regulation of the inflammatory process. In conclusion, we found that different doses of acute aerobic exercise induced a distinct and specific c-inflammamiR response, which may be associated with control of the exercise-induced inflammatory cascade. Our findings point to c-inflammamiRs as potential biomarkers of exercise-induced inflammation, and hence, exercise dose.

Docosahexaenoic acid modulates the enterocyte Caco-2 cell expression of microRNAs involved in lipid metabolism.

Consumption of the long-chain ω-3 (n-3) polyunsaturated fatty acid docosahexaenoic acid (DHA) is associated with a reduced risk of cardiovascular disease and greater chemoprevention. However, the mechanisms underlying the biologic effects of DHA remain unknown. It is well known that microRNAs (miRNAs) are versatile regulators of gene expression. Therefore, we aimed to determine if the beneficial effects of DHA may be modulated in part through miRNAs. Loss of dicer 1 ribonuclease type III (DICER) in enterocyte Caco-2 cells supplemented with DHA suggested that several lipid metabolism genes are modulated by miRNAs. Analysis of miRNAs predicted to target these genes revealed several miRNA candidates that are differentially modulated by fatty acids. Among the miRNAs modulated by DHA were miR-192 and miR-30c. Overexpression of either miR-192 or miR-30c in enterocyte and hepatocyte cells suggested an effect on the expression of genes related to lipid metabolism, some of which were confirmed by endogenous inhibition of these miRNAs. Our results show in enterocytes that DHA exerts its biologic effect in part by regulating genes involved in lipid metabolism and cancer. Moreover, this response is mediated through miRNA activity. We validate novel targets of miR-30c and miR-192 related to lipid metabolism and cancer including nuclear receptor corepressor 2, isocitrate dehydrogenase 1, DICER, caveolin 1, ATP-binding cassette subfamily G (white) member 4, retinoic acid receptor ß, and others. We also present evidence that in enterocytes DHA modulates the expression of regulatory factor X6 through these miRNAs. Alteration of miRNA levels by dietary components in support of their pharmacologic modulation might be valuable in adjunct therapy for dyslipidemia and other related diseases.