Research Article| Volume 264, P130-136, August 01, 2018

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Circulating microRNAs as emerging cardiac biomarkers responsive to acute exercise


      • Different doses of acute exercise induce specific profiles of circulating microRNAs proposed as biomarkers of heart disease.
      • Circulating microRNAs offer incremental diagnostic value to other cardiac biomarkers in the context of acute exercise.
      • In absence of cardiac damage or dysfunction after acute exercise, circulating microRNAs show “pseudo-disease” signatures.
      • Our results suggest a potential role of circulating microRNAs as mediators of cardiac response to acute exercise.



      Circulating microRNAs (c-miRNAs) are mediators of intercellular communication with great potential as cardiac biomarkers. The analysis of c-miRNAs in response to physiological stress, such as exercise, would provide valuable information for clinical practice and a deeper understanding of the molecular response to physical activity. Here, we analysed for the first time the acute exercise response of c-miRNAs reported as biomarkers of cardiac disease in a well-characterized cohort of healthy active adults.


      Blood samples were collected immediately before and after (0 h, 24 h, 72 h) a 10-km race, a half-marathon (HM) and a marathon (M). Serum RNA from 10-km and M samples was extracted and a panel of 74 miRNAs analysed using RT-qPCR. c-miRNA response was compared with a panel of nine cardiac biomarkers. Functional enrichment analysis was performed. Pre- and post-M echocardiographic analyses were carried out.


      Serum levels of all cardiac biomarkers were upregulated in a dose-dependent manner in response to exercise, even in the absence of symptoms or signs of cardiac injury. A deregulation in the profiles of 5 and 19 c-miRNAs was observed for 10-km and M, respectively. Each race induced a specific qualitative and quantitative alteration of c-miRNAs implicated in cardiac adaptions. Supporting their discriminative potential, a number of c-miRNAs previously associated with cardiac disease were undetectable or stable in response to exercise. Conversely, “pseudo-disease” signatures were also observed.


      c-miRNAs may be useful for the management of cardiac conditions in the context of acute aerobic exercise.

      Translational aspects of the work

      Circulating microRNAs could offer incremental diagnostic value to established and emerging cardiac biomarkers, such as hs-cTnT or NT-proBNP, in those patients with cardiac dysfunction symptoms after an acute bout of endurance exercise. Furthermore, circulating miRNAs could also show “pseudo-disease” signatures in response to acute exercise. Clinical practitioners should be aware of the impact caused by exercise in the interpretation of miRNA data.


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        • Scherr J.
        • Braun S.
        • Schuster T.
        • et al.
        72-h kinetics of high-sensitive troponin T and inflammatory markers after marathon.
        Med. Sci. Sports Exerc. 2011; 43: 1819-1827
        • Beermann J.
        • Piccoli M.T.
        • Viereck J.
        • Thum T.
        Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches.
        Physiol. Rev. 2016; 96: 1297-1325
        • Shan Z.
        • Qin S.
        • Li W.
        • et al.
        An endocrine genetic signal between blood cells and vascular smooth muscle cells: role of MicroRNA-223 in smooth muscle function and atherogenesis.
        J. Am. Coll. Cardiol. 2015; 65: 2526-2537
        • Bang C.
        • Batkai S.
        • Dangwal S.
        • et al.
        Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy.
        J. Clin. Invest. 2014; 124: 2136-2146
        • de Gonzalo-Calvo D.
        • Cenarro A.
        • Garlaschelli K.
        • et al.
        Translating the microRNA signature of microvesicles derived from human coronary artery smooth muscle cells in patients with familial hypercholesterolemia and coronary artery disease.
        J. Mol. Cell. Cardiol. 2017; 106: 55-67
        • Derda A.A.
        • Thum S.
        • Lorenzen J.M.
        • et al.
        Blood-based microRNA signatures differentiate various forms of cardiac hypertrophy.
        Int. J. Cardiol. 2015; 196: 115-122
        • Devaux Y.
        • Mueller M.
        • Haaf P.
        • et al.
        Diagnostic and prognostic value of circulating microRNAs in patients with acute chest pain.
        J. Intern. Med. 2015; 277: 260-271
        • de Gonzalo-Calvo D.
        • van der Meer R.W.
        • Rijzewijk L.J.
        • et al.
        Serum microRNA-1 and microRNA-133a levels reflect myocardial steatosis in uncomplicated type 2 diabetes.
        Sci. Rep. 2017; 7: 47
        • Oerlemans M.I.
        • Mosterd A.
        • Dekker M.S.
        • et al.
        Early assessment of acute coronary syndromes in the emergency department: the potential diagnostic value of circulating microRNAs.
        EMBO Mol. Med. 2012; 4: 1176-1185
        • Zeller T.
        • Keller T.
        • Ojeda F.
        • et al.
        Assessment of microRNAs in patients with unstable angina pectoris.
        Eur. Heart J. 2014; 35: 2106-2114
        • Carrick-Ranson G.
        • Hastings J.L.
        • Bhella P.S.
        • et al.
        The effect of lifelong exercise dose on cardiovascular function during exercise.
        J. Appl. Physiol. 2014; 116 (1985): 736-745
        • Miller F.L.
        • O'Connor D.P.
        • Herring M.P.
        • et al.
        Exercise dose, exercise adherence, and associated health outcomes in the TIGER study.
        Med. Sci. Sports Exerc. 2014; 46: 69-75
        • Mestdagh P.
        • Hartmann N.
        • Baeriswyl L.
        • et al.
        Evaluation of quantitative miRNA expression platforms in the microRNA quality control (miRQC) study.
        Nat. Methods. 2014; 11: 809-815
        • Blondal T.
        • Jensby Nielsen S.
        • Baker A.
        • et al.
        Assessing sample and miRNA profile quality in serum and plasma or other biofluids.
        Methods. 2013; 59: S1-6
        • Vlachos I.S.
        • Zagganas K.
        • Paraskevopoulou M.D.
        • et al.
        DIANA-miRPath v3.0: deciphering microRNA function with experimental support.
        Nucleic Acids Res. 2015; 43: W460-466
        • Legaz-Arrese A.
        • Lopez-Laval I.
        • George K.
        • et al.
        Impact of an endurance training program on exercise-induced cardiac biomarker release.
        Am. J. Physiol. Heart Circ. Physiol. 2015; 308: H913-920
        • Klinkenberg L.J.
        • Luyten P.
        • van der Linden N.
        • et al.
        Cardiac troponin T and I release after a 30-km run.
        Am. J. Cardiol. 2016; 118: 281-287
        • Neilan T.G.
        • Yoerger D.M.
        • Douglas P.S.
        • et al.
        Persistent and reversible cardiac dysfunction among amateur marathon runners.
        Eur. Heart J. 2006; 27: 1079-1084
        • Hanssen H.
        • Keithahn A.
        • Hertel G.
        • et al.
        Magnetic resonance imaging of myocardial injury and ventricular torsion after marathon running.
        Clin. Sci. (Lond.). 2011; 120: 143-152
        • Eijsvogels T.M.
        • Fernandez A.B.
        • Thompson P.D.
        Are there deleterious cardiac effects of acute and chronic endurance exercise?.
        Physiol. Rev. 2016; 96: 99-125
        • Weippert M.
        • Divchev D.
        • Schmidt P.
        • et al.
        Cardiac troponin T and echocardiographic dimensions after repeated sprint vs. moderate intensity continuous exercise in healthy young males.
        Sci. Rep. 2016; 624614
        • Nie J.
        • George K.
        • Duan F.
        • Tong T.K.
        • Tian Y.
        Histological evidence for reversible cardiomyocyte changes and serum cardiac troponin T elevation after exercise in rats.
        Phys. Rep. 2016; 4
        • de Gonzalo-Calvo D.
        • Davalos A.
        • Montero A.
        • et al.
        Circulating inflammatory miRNA signature in response to different doses of aerobic exercise.
        J. Appl. Physiol. 2015; 119 (1985): 124-134
        • Baggish A.L.
        • Park J.
        • Min P.K.
        • et al.
        Rapid upregulation and clearance of distinct circulating microRNAs after prolonged aerobic exercise.
        J. Appl. Physiol. 2014; 116 (1985): 522-531
        • Wang G.K.
        • Zhu J.Q.
        • Zhang J.T.
        • et al.
        Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans.
        Eur. Heart J. 2010; 31: 659-666
        • Whyte G.P.
        Clinical significance of cardiac damage and changes in function after exercise.
        Med. Sci. Sports Exerc. 2008; 40: 1416-1423
        • Pelliccia A.
        • Maron B.J.
        • Culasso F.
        • et al.
        Clinical significance of abnormal electrocardiographic patterns in trained athletes.
        Circulation. 2000; 102: 278-284
        • Shave R.
        • Baggish A.
        • George K.
        • et al.
        Exercise-induced cardiac troponin elevation: evidence, mechanisms, and implications.
        J. Am. Coll. Cardiol. 2010; 56: 169-176
        • Cheng C.
        • Wang Q.
        • You W.
        • Chen M.
        • Xia J.
        MiRNAs as biomarkers of myocardial infarction: a meta-analysis.
        PLoS One. 2014; 9e88566
        • Tijsen A.J.
        • Creemers E.E.
        • Moerland P.D.
        • et al.
        MiR423-5p as a circulating biomarker for heart failure.
        Circ. Res. 2010; 106: 1035-1039
        • Baggish A.L.
        • Hale A.
        • Weiner R.B.
        • et al.
        Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training.
        J. Physiol. 2011; 589: 3983-3994
        • Nielsen S.
        • Scheele C.
        • Yfanti C.
        • et al.
        Muscle specific microRNAs are regulated by endurance exercise in human skeletal muscle.
        J. Physiol. 2010; 588: 4029-4037
        • George K.
        • Whyte G.P.
        • Green D.J.
        • et al.
        The endurance athletes heart: acute stress and chronic adaptation.
        Br. J. Sports Med. 2012; 46: i29-36
        • Fernandes T.
        • Hashimoto N.Y.
        • Magalhaes F.C.
        • et al.
        Aerobic exercise training-induced left ventricular hypertrophy involves regulatory MicroRNAs, decreased angiotensin-converting enzyme-angiotensin ii, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin (1–7).
        Hypertension. 2011; 58: 182-189
        • Ma Z.
        • Qi J.
        • Meng S.
        • Wen B.
        • Zhang J.
        Swimming exercise training-induced left ventricular hypertrophy involves microRNAs and synergistic regulation of the PI3K/AKT/mTOR signaling pathway.
        Eur. J. Appl. Physiol. 2013; 113: 2473-2486
        • Silva D.A.
        • ND J.
        • Fernandes T.
        • Soci U.P.
        • Monteiro A.W.
        • Phillips M.I.
        • EM D.E.O.
        Swimming training in rats increases cardiac MicroRNA-126 expression and angiogenesis.
        Med. Sci. Sports Exerc. 2012; 44: 1453-1462
        • Liu X.
        • Xiao J.
        • Zhu H.
        • et al.
        miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling.
        Cell Metab. 2015; 21: 584-595
        • Eulalio A.
        • Mano M.
        • Dal Ferro M.
        • et al.
        Functional screening identifies miRNAs inducing cardiac regeneration.
        Nature. 2012; 492: 376-381
        • Chen I.Y.
        • Matsa E.
        • Wu J.C.
        Induced pluripotent stem cells: at the heart of cardiovascular precision medicine.
        Nat. Rev. Cardiol. 2016; 13: 333-349
        • Mooren F.C.
        • Viereck J.
        • Kruger K.
        • Thum T.
        Circulating microRNAs as potential biomarkers of aerobic exercise capacity.
        Am. J. Physiol. Heart Circ. Physiol. 2014; 306: H557-563