MiRNA126 - RGS16 - CXCL12 Cascade as a Potential Mechanism of Acute Exercise-Induced Precursor Cell Mobilization

Michelle Schmid, Helena Caria Martins, Gerhard Schratt, Julia M Kröpfl, Christina M Spengler, Michelle Schmid, Helena Caria Martins, Gerhard Schratt, Julia M Kröpfl, Christina M Spengler

Abstract

Acute exercise enhances circulating stem and precursor cells (CPCs) in the peripheral blood. The responsible mechanisms and molecular pathways, however, have not been fully identified. The aim of the present study was to investigate a pathway related to elevated levels of apoptotic peripheral blood mononuclear cells (MNCs) and their secretome. An increased uptake of miRNA126 in MNCs was suggested to lead to reduced levels of RGS16 mRNA and, in turn, an enhanced translation and secretion of CXCL12. Eighteen healthy, young men underwent two identical incremental cycling exercises of which the first served as control while the second was preceded by a 7-day-long antioxidative supplementation. Blood samples were collected at baseline (-10min) and several time points after exercise (0, 30, 90, 180, and 270min). Relative concentrations of miRNA126 in MNCs and CXCL12 levels in plasma were determined at all time points while RGS16 mRNA was assessed in MNCs at baseline and 30min after exercise. CXCL12 increased after exercise and strongly correlated with CPC numbers. MiRNA126 increased 30min and, to a lesser extent, also 180 and 270min after exercise but only with supplementation. RGS16 mRNA decreased 30min after exercise independent of the intervention. The amount of RGS16 mRNA inversely correlated with levels of miRNA126, but not with plasma CXCL12. In conclusion, even though plasma CXCL12 correlated with CPC numbers, the increase in CXCL12 cannot be explained by the increased concentration of miRNA126 and lower RGS16 mRNA in MNCs that would have allowed for an enhanced translation of CXCL12. Clinical Trial Registration: ClinicalTrials.gov, NCT03747913. Registered 20 November 2018, https://ichgcp.net/clinical-trials-registry/NCT03747913.

Keywords: CD34+/CD45dim cell mobilization; CXCL12; RGS16; acute exhaustive exercise; apoptosis; miRNA126; oxidative stress index; stem cell mobilization.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Schmid, Martins, Schratt, Kröpfl and Spengler.

Figures

Figure 1
Figure 1
Plasma CXCL12 concentrations in pg/ml (n=18). Values are mean±SD. Differences from baseline are indicated by *, with *p<0.05.
Figure 2
Figure 2
Relative quantification of miRNA126 to miRNA191 in MNCs using the ΔCt method (n=18). Bars include 50% of all data points while the line within the bars represents the median. Additionally, the mean is indicated by a “+”-sign in each bar. Whiskers represent minimum and maximum values with all individual data points being shown. Differences from baseline are indicated by *, with *p<0.05; **p<0.01.
Figure 3
Figure 3
Relative quantification of RGS16 mRNA to GAPDH mRNA in MNCs using the ΔCt method (n=17 for control intervention and n=18 for supplemented intervention). Bars include 50% of all data points while the line within the bars represents the median. Additionally, the mean is indicated by a “+”-sign in each bar. Whiskers represent minimum and maximum values with all individual data points being shown. Differences between the two time points are indicated by *, with *p<0.05.

References

    1. Agha N. H., Baker F. L., Kunz H. E., Graff R., Azadan R., Dolan C., et al. . (2018). Vigorous exercise mobilizes CD34+ hematopoietic stem cells to peripheral blood via the β2-adrenergic receptor. Brain Behav. Immun. 68, 66–75. doi: 10.1016/j.bbi.2017.10.001, PMID:
    1. Beer L., Mildner M., Gyöngyösi M., Ankersmit H. J. (2016). Peripheral blood mononuclear cell secretome for tissue repair. Apoptosis 21, 1336–1353. doi: 10.1007/s10495-016-1292-8, PMID:
    1. Cai Y., Yu X., Hu S., Yu J. (2009). A brief review on the mechanisms of miRNA regulation. Genomics Proteomics Bioinformatics 7, 147–154. doi: 10.1016/S1672-0229(08)60044-3, PMID:
    1. Chang E., Paterno J., Duscher D., Maan Z. N., Chen J. S., Januszyk M., et al. . (2015). Exercise induces SDF-1 mediated release of endothelial progenitor cells with increased Vasculogenic function. Plast. Reconstr. Surg. 135:340. doi: 10.1097/PRS.0000000000000917
    1. Da Silva N. D., Jr., Roseguini B. T., Chehuen M., Fernandes T., Mota G. F., Martin P. K., et al. . (2015). Effects of oral N-acetylcysteine on walking capacity, leg reactive hyperemia, and inflammatory and angiogenic mediators in patients with intermittent claudication. Am. J. Phys. Heart Circ. Phys. 309, H897–H905. doi: 10.1152/ajpheart.00158.2015
    1. Dill D. B., Costill D. L. (1974). Calculation of percentage changes in volumes of blood, plasma, and red cells in dehydration. J. Appl. Physiol. 37, 247–248. doi: 10.1152/jappl.1974.37.2.247, PMID:
    1. Fish J. E., Santoro M. M., Morton S. U., Yu S., Yeh R.-F., Wythe J. D., et al. . (2008). miR-126 regulates angiogenic signaling and vascular integrity. Dev. Cell 15, 272–284. doi: 10.1016/j.devcel.2008.07.008, PMID:
    1. Fish J. E., Srivastava D. (2009). MicroRNAs: opening a new vein in angiogenesis research. Sci. Signal. 2:pe1. doi: 10.1126/scisignal.252pe1
    1. Hass R., Kasper C., Böhm S., Jacobs R. (2011). Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun. Signal. 9, 1–14. doi: 10.1186/1478-811X-9-12
    1. Jorbenadze R., Schleicher E., Bigalke B., Stellos K., Gawaz M. (2014). Expression of platelet-bound stromal-cell derived factor-1 (SDF-1) and number of CD34+ progenitor cells in patients with congestive heart failure. Platelets 25, 409–415. doi: 10.3109/09537104.2013.829913, PMID:
    1. Krüger K., Mooren F. C. (2014). Exercise-induced leukocyte apoptosis. Exerc. Immunol. Rev. 20, 117–134. PMID:
    1. Monaco G., Lee B., Xu W., Mustafah S., Hwang Y. Y., Carre C., et al. . (2019). RNA-Seq signatures normalized by mRNA abundance allow absolute deconvolution of human immune cell types. Cell Rep. 26, 1627.e7–1640.e7. doi: 10.1016/j.celrep.2019.01.041, PMID:
    1. Montgomery R., Paterson A., Williamson C., Florida-James G., Ross M. D. (2019). Blood flow restriction exercise attenuates the exercise-induced endothelial progenitor cell response in healthy, young men. Front. Physiol. 10:447. doi: 10.3389/fphys.2019.00447, PMID:
    1. Niemiro G. M., Edwards T., Barfield J., Beals J. W., Broad E. M., Motl R. W., et al. . (2018). Circulating progenitor cell response to exercise in wheelchair racing athletes. Med. Sci. Sports Exerc. 50, 88–97. doi: 10.1249/MSS.0000000000001402, PMID:
    1. Niemiro G. M., Parel J., Beals J., Van Vliet S., Paluska S. A., Moore D. R., et al. . (2017). Kinetics of circulating progenitor cell mobilization during submaximal exercise. J. Appl. Physiol. 122, 675–682. doi: 10.1152/japplphysiol.00936.2016, PMID:
    1. Phaneuf S., Leeuwenburgh C. (2001). Apoptosis and exercise. Med. Sci. Sports Exerc. 33, 393–396. doi: 10.1097/00005768-200103000-00010
    1. Ratajczak M. (2015). A novel view of the adult bone marrow stem cell hierarchy and stem cell trafficking. Leukemia 29, 776–782. doi: 10.1038/leu.2014.346, PMID:
    1. Ribeiro F., Ribeiro I. P., Gonçalves A. C., Alves A. J., Melo E., Fernandes R., et al. . (2017). Effects of resistance exercise on endothelial progenitor cell mobilization in women. Sci. Rep. 7, 1–9. doi: 10.1038/s41598-017-18156-6
    1. Ross M. D., Malone E. M., Simpson R., Cranston I., Ingram L., Wright G. P., et al. . (2017). Lower resting and exercise-induced circulating angiogenic progenitors and angiogenic T cells in older men. Am. J. Phys. Heart Circ. Phys. 314, 392–402. doi: 10.1152/ajpheart.00592.2017
    1. Sánchez-Martín L., Estecha A., Samaniego R., Sánchez-Ramón S., Vega M. Á., Sánchez-Mateos P. (2011). The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression. Blood 117, 88–97. doi: 10.1182/blood-2009-12-258186
    1. Schmid M., Gruber H.-J., Kröpfl J. M., Spengler C. M. (2020). Acute exercise-induced oxidative stress does not affect immediate or delayed precursor cell mobilization in healthy young males. Front. Physiol. 11:1314. doi: 10.3389/fphys.2020.577540
    1. Schmid M., Kröpfl J., Spengler C. (2021). Changes in circulating stem and progenitor cell numbers following acute exercise in healthy human subjects: a systematic review and meta-analysis. Stem Cell Rev. Rep. 17, 1091–1120. doi: 10.1007/s12015-020-10105-7, PMID:
    1. Sugiyama T., Kohara H., Noda M., Nagasawa T. (2006). Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25, 977–988. doi: 10.1016/j.immuni.2006.10.016, PMID:
    1. Timmermans F., Plum J., Yöder M. C., Ingram D. A., Vandekerckhove B., Case J. (2009). Endothelial progenitor cells: identity defined? J. Cell. Mol. Med. 13, 87–102. doi: 10.1111/j.1582-4934.2008.00598.x, PMID:
    1. Uhlemann M., Möbius-Winkler S., Fikenzer S., Adam J., Redlich M., Möhlenkamp S., et al. . (2014). Circulating microRNA-126 increases after different forms of endurance exercise in healthy adults. Eur. J. Prev. Cardiol. 21, 484–491. doi: 10.1177/2047487312467902, PMID:
    1. Van Craenenbroeck E. M., Beckers P. J., Possemiers N. M., Wuyts K., Frederix G., Hoymans V. Y., et al. . (2010). Exercise acutely reverses dysfunction of circulating angiogenic cells in chronic heart failure. Eur. Heart J. 31, 1924–1934. doi: 10.1093/eurheartj/ehq058, PMID:
    1. Van Craenenbroeck E. M., Bruyndonckx L., Van Berckelaer C., Hoymans V. Y., Vrints C. J., Conraads V. M. (2011). The effect of acute exercise on endothelial progenitor cells is attenuated in chronic heart failure. Eur. J. Appl. Physiol. 111, 2375–2379. doi: 10.1007/s00421-011-1843-1, PMID:
    1. Yin Y., Huang L., Zhao X., Fang Y., Yu S., Zhao J., et al. . (2007). AMD3100 mobilizes endothelial progenitor cells in mice, but inhibits its biological functions by blocking an autocrine/paracrine regulatory loop of stromal cell derived factor-1 in vitro. J. Cardiovasc. Pharmacol. 50, 61–67. doi: 10.1097/FJC.0b013e3180587e4d, PMID:
    1. Zaldivar F., Eliakim A., Radom-Aizik S., Leu S.-Y., Cooper D. M. (2007). The effect of brief exercise on circulating CD34+ stem cells in early and late pubertal boys. Pediatr. Res. 61, 491–495. doi: 10.1203/pdr.0b013e3180332d36, PMID:
    1. Zernecke A., Bidzhekov K., Noels H., Shagdarsuren E., Gan L., Denecke B., et al. . (2009). Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci. Signal. 2:81. doi: 10.1126/scisignal.2000610

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