{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:08:47Z","timestamp":1790633327745,"version":"4.1.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T00:00:00Z","timestamp":1632700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["1194918N"],"award-info":[{"award-number":["1194918N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006282","name":"Koning Boudewijnstichting","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006282","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Exercise training improves VO<jats:sub>2<\/jats:sub>peak in heart failure with reduced ejection fraction (HFrEF), but the effect is highly variable as it is dependent on peripheral adaptations. We evaluated changes in plasma-derived miRNAs by acute and chronic exercise to investigate whether these can mechanistically be involved in the variability of exercise-induced adaptations.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Twenty-five male HFrEF patients (left ventricular ejection fraction &amp;lt; 40%, New York Heart Association class \u2265 II) participated in a 15-week combined strength and aerobic training program. The effect of training on plasma miRNA levels was compared to 21 male age-matched sedentary HFrEF controls. Additionally, the effect of a single acute exercise bout on plasma miRNA levels was assessed. Levels of 5 miRNAs involved in pathways relevant for exercise adaptation (miR-23a, miR-140, miR-146a, miR-191, and miR-210) were quantified using RT-qPCR and correlated with cardiopulmonary exercise test (CPET), echocardiographic, vascular function, and muscle strength variables.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Expression levels of miR-146a decreased with training compared to controls. Acute exercise resulted in a decrease in miR-191 before, but not after training. Baseline miR-23a predicted change in VO<jats:sub>2<\/jats:sub>peak independent of age and left ventricular ejection fraction (LVEF). Baseline miR-140 was independently correlated with change in load at the respiratory compensation point and change in body mass index, and baseline miR-146a with change in left ventricular mass index.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Plasma-derived miRNAs may reflect the underlying mechanisms of exercise-induced adaptation. In HFrEF patients, baseline miR-23a predicted VO<jats:sub>2<\/jats:sub>peak response to training. Several miRNAs were influenced by acute or repeated exercise. These findings warrant exploration in larger patient populations and further mechanistic <jats:italic>in vitro<\/jats:italic> studies on their molecular involvement.<\/jats:p>","DOI":"10.3389\/fphys.2021.736494","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T07:16:47Z","timestamp":1632727007000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Plasma-Derived microRNAs Are Influenced by Acute and Chronic Exercise in Patients With Heart Failure With Reduced Ejection Fraction"],"prefix":"10.3389","volume":"12","author":[{"given":"Isabel","family":"Witvrouwen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas B.","family":"Gevaert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Possemiers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert","family":"Ectors","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tibor","family":"Stoop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge","family":"Goovaerts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evi","family":"Boeren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Hens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Beckers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Vorlat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hein","family":"Heidbuchel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amaryllis H.","family":"Van Craenenbroeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emeline M.","family":"Van Craenenbroeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,27]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"H72","DOI":"10.1152\/ajpheart.00470.2016","article-title":"Molecular effects of exercise training in patients with cardiovascular disease: focus on skeletal muscle, endothelium, and myocardium.","volume":"313","author":"Adams","year":"2017","journal-title":"Am. J. Physiol. Hear. Circ. Physiol."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/ehf2.13405","article-title":"Ubiquitin-proteasome-system and enzymes of energy metabolism in skeletal muscle of patients with HFpEF and HFrEF.","volume":"2021","author":"Adams","year":"2021","journal-title":"ESC Hear. Fail."},{"key":"B3","doi-asserted-by":"publisher","first-page":"78","DOI":"10.14715\/cmb\/2017.63.3.15","article-title":"Evaluation of relationship between aerobic fitness level and range of isocapnic buffering periods during incremental exercise test.","volume":"63","author":"Algul","year":"2017","journal-title":"Cell Mol. Biol."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/7163057","article-title":"MiR-146a Attenuates Sepsis-Induced Myocardial Dysfunction by Suppressing IRAK1 and TRAF6 via Targeting ErbB4 Expression.","volume":"2018","author":"An","year":"2018","journal-title":"Oxid. Med. Cell Longev"},{"key":"B5","doi-asserted-by":"crossref","first-page":"3983","DOI":"10.1113\/jphysiol.2011.213363","article-title":"Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training.","volume":"589","author":"Baggish","year":"2011","journal-title":"J. Physiol."},{"key":"B6","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1152\/japplphysiol.01141.2013","article-title":"Rapid upregulation and clearance of distinct circulating microRNAs after prolonged aerobic exercise.","volume":"116","author":"Baggish","year":"2014","journal-title":"J. Appl. Physiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1249\/MSS.0000000000001429","article-title":"Absence of fitness improvement is associated with outcomes in heart failure patients.","volume":"50","author":"Bakker","year":"2018","journal-title":"Med. Sci. Sport. Exerc."},{"key":"B8","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1177\/1741826711400664","article-title":"Impact of exercise testing mode on exercise parameters in patients with chronic heart failure.","volume":"19","author":"Beckers","year":"2011","journal-title":"Eur. J. Prev. Cardiol."},{"key":"B9","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/0735-1097(95)00267-1","article-title":"Low intensity exercise training in patients with chronic heart failure.","volume":"26","author":"Belardinelli","year":"1995","journal-title":"J. Am. Coll. Cardiol."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0057496","article-title":"Circulating MicroRNAs and aerobic fitness - The HUNT-Study.","volume":"8","author":"Bye","year":"2013","journal-title":"PLoS One"},{"key":"B11","doi-asserted-by":"publisher","first-page":"276","DOI":"10.3389\/fgene.2016.00196","article-title":"Muscle-Enriched MicroRNAs isolated from whole blood are regulated by exercise and are potential biomarkers of cardiorespiratory fitness.","volume":"7","author":"Denham","year":"2016","journal-title":"Front. Genet."},{"key":"B12","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.18632\/aging.101948","article-title":"MiR-191 inhibit angiogenesis after acute ischemic stroke targeting VEZF1.","volume":"11","author":"Du","year":"2019","journal-title":"Aging"},{"key":"B13","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1016\/S0735-1097(99)00101-1","article-title":"Capillary density of skeletal muscle. a contributing mechanism for exercise intolerance in class II\u2013III chronic heart failure independent of other peripheral alterations.","volume":"33","author":"Duscha","year":"1999","journal-title":"JACC"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1177\/2047487319877716","article-title":"Towards a personalised approach in exercise-based cardiovascular rehabilitation: How can translational research help? A \u2018call to action\u2019 from the Section on Secondary Prevention and Cardiac Rehabilitation of the European Association of Preventive Cardiolo.","volume":"2019","author":"Gevaert","year":"2019","journal-title":"Eur. J. Prev. Cardiol."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0193173","article-title":"MicroRNA profiling in plasma samples using qPCR arrays: Recommendations for correct analysis and interpretation.","volume":"13","author":"Gevaert","year":"2018","journal-title":"PLoS One"},{"key":"B16","doi-asserted-by":"publisher","first-page":"3321","DOI":"10.1096\/fj.201601263R","article-title":"MIR-191 suppresses angiogenesis by activation of NF-kB signaling.","volume":"31","author":"Gu","year":"2017","journal-title":"FASEB J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12967-016-0974-x","article-title":"miRNAs and sports: Tracking training status and potentially confounding diagnoses.","volume":"14","author":"Hecksteden","year":"2016","journal-title":"J. Transl. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1161\/CIRCULATIONAHA.116.024171","article-title":"Inhibition of MicroRNA-146a and overexpression of its target dihydrolipoyl succinyltransferase protect against pressure overload-induced cardiac hypertrophy and dysfunction.","volume":"136","author":"Heggermont","year":"2017","journal-title":"Circulation"},{"key":"B19","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1249\/MSS.0000000000001409","article-title":"Temporal response of angiogenesis and hypertrophy to resistance training in young men.","volume":"50","author":"Holloway","year":"2018","journal-title":"Med. Sci. Sports Exerc."},{"key":"B20","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1152\/physrev.1992.72.2.369","article-title":"Angiogenesis in skeletal and cardiac muscle.","volume":"72","author":"Hudlicka","year":"1992","journal-title":"Physiol. Rev."},{"key":"B21","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1113\/jphysiol.1979.sp012938","article-title":"Effects of endurance training on muscle fibre ATP-ase activity, capillary supply and mitochondrial content in man.","volume":"294","author":"Ingjer","year":"1979","journal-title":"J. Physiol."},{"key":"B22","author":"Jones","year":"1982","journal-title":"Clinical exercise testing."},{"key":"B23","first-page":"307","article-title":"The effects of training on heart rate; a longitudinal study.","volume":"35","author":"Karvonen","year":"1957","journal-title":"Ann. Med. Exp. Biol. Fenn."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvz215","article-title":"Circular RNA circRNA_000203 aggravates cardiac hypertrophy via suppressing miR-26b-5p and miR-140-3p binding to Gata4.","volume":"2019","author":"Li","year":"2019","journal-title":"Cardiovasc. Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"C189","DOI":"10.1152\/ajpcell.00419.2018","article-title":"MicroRNA-140 inhibits skeletal muscle glycolysis and atrophy in endotoxin-induced sepsis in mice via the WNT signaling pathway.","volume":"317","author":"Liu","year":"2019","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.preghy.2019.02.001","article-title":"Low-flow mediated constriction as a marker of endothelial function in healthy pregnancy and preeclampsia: a pilot study.","volume":"17","author":"Mannaerts","year":"2019","journal-title":"Pregnancy Hypertens."},{"key":"B27","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1152\/physiolgenomics.00112.2017","article-title":"Identification of human skeletal muscle miRNA related to strength by high-throughput sequencing.","volume":"50","author":"Mitchell","year":"2018","journal-title":"Physiol. Genomics"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0087308","article-title":"The miRNA plasma signature in response to acute aerobic exercise and endurance training.","volume":"9","author":"Nielsen","year":"2014","journal-title":"PLoS One"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-020-64365-x","article-title":"Different exercise training modalities produce similar endothelial function improvements in individuals with prehypertension or hypertension: a randomized clinical trial Exercise, endothelium and blood pressure.","volume":"10","author":"Pedralli","year":"2020","journal-title":"Sci. Rep."},{"key":"B30","doi-asserted-by":"crossref","first-page":"3","DOI":"10.4161\/epi.27473","article-title":"Non-coding RNAs as direct and indirect modulators of epigenetic regulation.","volume":"9","author":"Peschansky","year":"2014","journal-title":"Epigenetics"},{"key":"B31","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1097\/HJR.0b013e3283361dc5","article-title":"Exercise intolerance in chronic heart failure: mechanisms and therapies.","volume":"17","author":"Piepoli","year":"2010","journal-title":"Part I. Eur. J. Prev. Cardiol."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013515","article-title":"Selective release of MicroRNA species from normal and malignant mammary epithelial cells.","volume":"5","author":"Pigati","year":"2010","journal-title":"PLoS One"},{"key":"B33","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1093\/eurheartj\/ehw128","article-title":"2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.","volume":"37","author":"Ponikowski","year":"2016","journal-title":"Eur. Heart J."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2019.144319","article-title":"MicroRNA-23a suppresses the apoptosis of inflammatory macrophages and foam cells in atherogenesis by targeting HSP90.","volume":"729","author":"Qiao","year":"2020","journal-title":"Gene"},{"key":"B35","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1159\/000461596","article-title":"Exogenous miRNA-146a Enhances the therapeutic efficacy of human mesenchymal stem cells by increasing vascular endothelial growth factor secretion in the ischemia\/reperfusion-injured heart.","volume":"54","author":"Seo","year":"2017","journal-title":"J. Vasc. Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1093\/abbs\/gmx052","article-title":"MIR-146a-5p acts as a negative regulator of TGF-\u03b2 signaling in skeletal muscle after acute contusion.","volume":"49","author":"Sun","year":"2017","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"B37","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1161\/CIRCHEARTFAILURE.108.775460","article-title":"Absence of exercise capacity improvement after exercise training program: a strong prognostic factor in patients with chronic heart failure.","volume":"1","author":"Tabet","year":"2008","journal-title":"Circ. Heart Fail."},{"key":"B38","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.pcad.2018.08.006.Meta-analysis","article-title":"Meta-analysis of exercise training on left ventricular ejection fraction in heart failure with reduced ejection fraction: a 10-year update.","volume":"62","author":"Tucker","year":"2019","journal-title":"Prog. Cardiovasc. Dis."},{"key":"B39","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1152\/ajpheart.00346.2015","article-title":"Plasma levels of microRNA in chronic kidney disease: patterns in acute and chronic exercise.","volume":"309","author":"Van Craenenbroeck","year":"","journal-title":"Am. J. Physiol. Hear. Circ. Physiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1053\/j.ajkd.2015.03.015","article-title":"Effect of moderate aerobic exercise training on endothelial function and arterial stiffness in CKD Stages 3-4: a randomized controlled trial.","volume":"66","author":"Van Craenenbroeck","year":"","journal-title":"Am. J. Kidney Dis."},{"key":"B41","doi-asserted-by":"publisher","first-page":"H1876","DOI":"10.1152\/ajpheart.00341.2015","article-title":"Effects of aerobic interval training and continuous training on cellular markers of endothelial integrity in coronary artery disease: A SAINTEX-CAD substudy.","volume":"309","author":"Van Craenenbroeck","year":"","journal-title":"Am. J. Physiol. Hear. Circ. Physiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1007\/s00395-010-0105-4","article-title":"Exercise training improves function of circulating angiogenic cells in patients with chronic heart failure.","volume":"105","author":"Van Craenenbroeck","year":"2010","journal-title":"Basic Res. Cardiol."},{"key":"B43","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/ejhf.495","article-title":"MicroRNAs in heart failure: from biomarker to target for therapy.","volume":"18","author":"Vegter","year":"2016","journal-title":"Eur. J. Heart Fail."},{"key":"B44","doi-asserted-by":"publisher","first-page":"38456","DOI":"10.1074\/jbc.M111.271270","article-title":"Translational suppression of atrophic regulators by MicroRNA-23a integrates resistance to skeletal muscle atrophy.","volume":"286","author":"Wada","year":"2011","journal-title":"J. Biol. Chem."},{"key":"B45","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1074\/jbc.M111.266940","article-title":"Cardiac hypertrophy is positively regulated by microRNA miR-23a.","volume":"287","author":"Wang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B46","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1093\/cvr\/cvw039","article-title":"The multifactorial nature of microRNAs in vascular remodelling.","volume":"110","author":"Welten","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/0034-5687(89)90076-5","article-title":"Ventilatory control of the \u201cisocapnic buffering\u201d region in rapidly-incremental exercise.","volume":"76","author":"Whipp","year":"1989","journal-title":"Respir. Physiol."},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1093\/eurjpc\/zwaa142","article-title":"Circulating microRNA as predictors for exercise response in heart failure with reduced ejection fraction.","volume":"2021","author":"Witvrouwen","year":"2021","journal-title":"Eur. J. Prev. Cardiol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/2047487319838221","article-title":"Exercise training in women with cardiovascular disease: differential response and barriers \u2013 review and perspective.","volume":"2019","author":"Witvrouwen","year":"2019","journal-title":"Eur. J. Prev. Cardiol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"12414","DOI":"10.18632\/oncotarget.6966","article-title":"Circulating miR-21, miR-378, and miR-940 increase in response to an acute exhaustive exercise in chronic heart failure patients.","volume":"7","author":"Xu","year":"2016","journal-title":"Oncotarget"},{"key":"B51","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1080\/15384101.2018.1480207","article-title":"Adipose-derived stem cell-derived microvesicle-released miR-210 promoted proliferation, migration and invasion of endothelial cells by regulating RUNX3.","volume":"17","author":"Zheng","year":"2018","journal-title":"Cell Cycle"},{"key":"B52","doi-asserted-by":"publisher","first-page":"8287","DOI":"10.1073\/pnas.1105254108","article-title":"Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23\u223c27\u223c24 clusters.","volume":"108","author":"Zhou","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"B53","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep25272","article-title":"Up-regulation of FGFBP1 signaling contributes to MIR-146a-induced angiogenesis in human umbilical vein endothelial cells.","volume":"6","author":"Zhu","year":"2016","journal-title":"Sci. Rep."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.736494\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T07:16:57Z","timestamp":1632727017000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.736494\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,27]]},"references-count":53,"alternative-id":["10.3389\/fphys.2021.736494"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.736494","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,27]]},"article-number":"736494"}}