3. MicroRNAs profile and type of trainingEndurance versus strength trainingThe term endurance training generally refers to aerobic training. As a result of endurance training, many changes are observed in the cardiovascular system as well as in the skeletal muscle system, and these changes may affect other systems. Long-term endurance training induces many physiological adaptations in both central and peripheral systems. In case of physiological adaptations in central cardiovascular system, it involves mainly decreased heart rate, increased stroke volume of the heart97 (Noakes 2000) as well as increased blood plasma volume without any major changes in red blood cell count which reduces blood viscosity and increases cardiac output. Moreover, this type of training is connected to total mitochondrial volume increases in the muscle fibres, and increases of maximal oxygen consumption (VO2 max)97 (Noakes 2000).In contrast, strength training is a type of physical exercise specializing in the use of resistance to induce muscular contraction which shapes the strength, anaerobic endurance, and skeletal muscle mass. When performed appropriately, strength training can provide significant functional benefits and improvement in overall health and well-being, including increased bone strength and muscle growth, improved joint function and reduced potential for injury98 (Shaw & Shaw 2014). Additionally, this type of training may increase bone density, muscles metabolism, and total body fitness99 (Shaw & Shaw 2009). Moreover, it improves cardiac function and lipoprotein lipid profiles, including elevated high-density lipoprotein (HDL) cholesterol which has been described as beneficial for health100 (Shaw & Shaw 2008).Increased physical activity has been associated with altered levels of circulating miRNAs (ci-miRNAs)45, 91 (Nielsen et al. 2010; Nielsen et al. 2014). It was highlighted that there was a significantly altered expression of selected ci-miRNAs in response to endurance or strength exercise interventions91 (Nielsen et al. 2014). Endurance exercise is a modulator of skeletal muscle miRNA expression. Following 12 weeks of endurance training, expression levels of several myomiRs, miR-1, miR-133a, miR-133b and miR-206, were significantly down-regulated, and returned to pre-training baseline expression levels in 2 weeks after the completion of training45 (Nielsen et al. 2010). In contrast, 10 days of endurance training increased miR-1, concomitantly with an increase in miR-29b and a decrease in miR-31 levels46 (Russell et al. 2013). With respect to a single bout of endurance exercise, miR-1 and miR-133a levels increased in the untrained state, however this acute response was not observed in the trained state46 (Russell et al. 2013). In addition, it was observed that in the 3 hour-period following a single bout of endurance exercise, miR-1, -133a, -133-b and miR-181a were all increased; in contrast miR-9, -23a, -23b and -31 were decreased46 (Russell et al. 2013).Studies have reported a significant difference in circulating miR-222 levels between male endurance versus strength athletes, as compared to age-matched untrained control group16, 19, 101 (Polakovi?ová et al. 2016; Silva et al. 2017; Wardle et al. 2015). Moreover, in endurance athletes, plasma levels of miR-21, miR-146a and miR-221, as well as miR-222, were significantly higher than in strength athletes101 (Wardle et al. 2015).Plasma miR-222 levels positively correlated with height, weight, body mass index (BMI) as well as muscle and fat mass101, 102 (Wardle et al. 2015; Cui et al. 2017). Interestingly, plasma miR-222 levels positively correlated with a strength-related performance measure, isokinetic leg flexion peak torque at various contraction velocities101 (Wardle et al. 2015). On the other hand, plasma miR-21 levels were not associated with anthropometric parameters, but negatively correlated with a subset of strength/power and endurance-related coefficients in both types (endurance and strength) of training. Plasma miR-146a and miR-221 levels positively correlated with height, muscle mass, fat mass and negatively correlated with BMI101 (Wardle et al. 2015).In addition, different endurance exercise protocols lead to an increase in miR-126 level where the plasma concentration of miR-126 was proposed as a novel marker for endothelial damage as it is highly and stably expressed in this cell type103 (Uhlemann et al. 2014). Exercise modulates mobilization of endothelial progenitor cells from the bone marrow allowing repair of the damaged endothelial cell layer but little is known about the influence of different type of exercise. This study suggested that increased endurance exercise leads to damage of the endothelial cell layer 103, 104 (Uhlemann et al. 2014; Lenk et al. 2011). Moreover, Nielsen et al. (2010) observed that miR-1 and miR-133a levels increases following a single bout of endurance exercise45. The authors hypothesized that repeated bouts of endurance training would lead to an increase in these myomiRs in human skeletal muscle. However, following 12 weeks of high intensity endurance training, the two studied myomiRs were downregulated. Nonetheless, this increase is partially in agreement with the results of another study performed on animal model. For instance in mice, the expression of miR-1 has been increased following forced treadmill running45, 105 (Nielsen et al. 2010; Safdar et al. 2009), and it has been preserved at high level after finishing the exercising. Furthermore, miR-486 regulates insulin-dependent glucose uptake in metabolic tissues, such as skeletal muscle, and this may be associated with the negative correlation between circulating miR-486 and VO2 max93 (Small et al. 2010). It should be stressed that differences in skeletal muscle phenotype have been associated with differences in miRNA expression levels and with genetic differences in miRNA binding sites to target genes involved in muscle phenotype. In addition, levels of several other miRNAs in skeletal muscle have been shown to change following short acute endurance exercise and following systematic endurance exercises45, 46, 101 (Nielsen et al. 2010; Russell et al. 2013, Wardle et al. 2015). Thus, the observation of fluctuations in miRNAs expression profiles (see Fig 3.) in response to many different types of training may be reflective of skeletal muscle adaptation responses, which is further influenced by complex net metabolic and genetic factors. Figure 3. Differences in circulating-miRNA (c-miRNA) levels are characteristic. These c-miRNAs (miRNA-9, miRNA-21, miRNA-23a/b, miRNA-31, miRNA-126, miRNA-146a and miRNA-181a) differ between endurance- and strength training. In endurance training miRNA-486 expression correlates with VO2 max, IAT. Moreover miRNA-1, miRNA-133a/b, miRNA-206 and miRNA-29b are common for endurance- and strength training. In endurance training miRNA-1, miRNA-133a/b, expression correlates with VO2 max, IATCONCLUSIONSThere is growing evidence suggesting that miRNAs are regulators of myogenesis and adaptive responses to exercise. Their expression levels change following a single bout of exercise and exercise training. The identification of ci-miRNAs and their regulation following exercise and in disease, suggests that they may be useful biomarkers of health and adaptation to treatment interventions. Selective activation and/or downregulation of the AMPK-PGC-1? or/and Akt-mTOR signaling pathways by miRNA is important in the context of physical exercise. These observations imply that miRNAs might be amenable to therapeutic intervention. MicroRNAs should be considered as candidate biomarkers related to the type of training, where some of these parameters correlate with exercise capacity, and/or anthropometric characteristics, and/or biochemical markers. Currently, little is known about how changes in skeletal muscle or ci-miRNAs influence, either directly or indirectly, skeletal muscle regeneration, size, function, metabolism and consequently the whole body health. Further studies must investigate the correlation of miRNA expression profiles with recognized physiological or biochemical markers as well as the underlying mechanisms to better understand the function of the implicated miRNAs within the cellular environment.