{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T22:05:27Z","timestamp":1778018727067,"version":"3.51.4"},"reference-count":42,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,15]],"date-time":"2025-02-15T00:00:00Z","timestamp":1739577600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical University of Bialystok","award":["SUB\/1\/DN\/20\/003\/1124"],"award-info":[{"award-number":["SUB\/1\/DN\/20\/003\/1124"]}]},{"name":"Medical University of Bialystok","award":["SUB\/1\/DN\/22\/001\/1124"],"award-info":[{"award-number":["SUB\/1\/DN\/22\/001\/1124"]}]},{"name":"Medical University of Bialystok","award":["SUB\/1\/DN\/19\/002\/1124"],"award-info":[{"award-number":["SUB\/1\/DN\/19\/002\/1124"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Atrial fibrillation (AF) is associated with energetic deficiency and oxidative stress due to mitochondrial dysfunction, resulting in electric remodeling. Long-term treatment was found to ameliorate mitochondrial function and decrease inducibility in animal models. No studies examine the short-term effect of SGLT-2 inhibitors administration in AF. In the present study, the samples of the right atrial appendage collected from 10 patients subjected to elective cardiac surgery were sliced and incubated in a control buffer (EMPA 0), 0.2 \u00b5mol\/L empagliflozin (EMPA 0.2), or 1.0 \u00b5mol\/L (EMPA 1). The expression of mitochondrial biogenesis, fission, and fusion proteins was measured by Western blot after 30 min of electrical stimulation (control\u20141 Hz or tachypacing\u20145 Hz). The PGC-1\u03b1 protein expression was increased after 30 min of stimulation with 1 Hz when incubated under a higher concentration of empagliflozin. After tachypacing, EMPA 0.2 increased PGC-1\u03b1, while EMPA 1.0 upregulated NRF-1. Both concentrations increased NRF-2 during control stimulation. The oxygen consumption was higher in AF, and was decreased by SGLT-2i. Empagliflozin exerts dynamic effects on the expression of PGC-1\u03b1 and other proteins involved in mitochondrial function and oxidative stress in cardiomyocytes and may modulate cellular response to tachycardia.<\/jats:p>","DOI":"10.3390\/ijms26041664","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T03:41:47Z","timestamp":1739763707000},"page":"1664","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Influence of Empagliflozin on the Expression of Mitochondrial Regulatory Proteins in Human Myocardium in an Ex Vivo Model of Short-Term Atrial Tachypacing"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0974-7138","authenticated-orcid":false,"given":"Pawe\u0142","family":"Muszy\u0144ski","sequence":"first","affiliation":[{"name":"Department of General and Experimental Pathology, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Cie\u015bli\u0144ska","sequence":"additional","affiliation":[{"name":"Department of General and Experimental Pathology, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6538-1049","authenticated-orcid":false,"given":"Magdalena","family":"Dziemidowicz","sequence":"additional","affiliation":[{"name":"Department of General and Experimental Pathology, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"El\u017cbieta","family":"Bonda-Ostaszewska","sequence":"additional","affiliation":[{"name":"Institute of Biology, University of Bialystok, Cio\u0142kowskiego 1J, 15-245 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomasz","family":"Hirnle","sequence":"additional","affiliation":[{"name":"Department of Cardiosurgery, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8735-1572","authenticated-orcid":false,"given":"Tomasz Andrzej","family":"Bonda","sequence":"additional","affiliation":[{"name":"Department of General and Experimental Pathology, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100157","DOI":"10.1016\/j.lanepe.2021.100157","article-title":"Atrial fibrillation epidemiology, disparity and healthcare contacts: A population-wide study of 5.6 million individuals","volume":"7","author":"Chung","year":"2021","journal-title":"Lancet Reg. Health Eur."},{"key":"ref_2","first-page":"213","article-title":"Epidemiology of atrial fibrillation: European perspective","volume":"6","author":"Lercari","year":"2014","journal-title":"Clin. Epidemiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1124\/pr.117.014183","article-title":"Mechanisms and Drug Development in Atrial Fibrillation","volume":"70","author":"Calvo","year":"2018","journal-title":"Pharmacol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12933-022-01480-1","article-title":"Direct cardiac effects of SGLT2 inhibitors","volume":"21","author":"Chen","year":"2022","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1161\/CIRCRESAHA.120.316363","article-title":"Molecular Basis of Atrial Fibrillation Pathophysiology and Therapy: A Translational Perspective","volume":"127","author":"Nattel","year":"2020","journal-title":"Circ. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e145","DOI":"10.1097\/FJC.0000000000001183","article-title":"Association of SGLT2 Inhibitors With Risk of Atrial Fibrillation and Stroke in Patients With and Without Type 2 Diabetes: A Systemic Review and Meta-Analysis of Randomized Controlled Trials","volume":"79","author":"Zheng","year":"2022","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/S0140-6736(22)01429-5","article-title":"SGLT-2 inhibitors in patients with heart failure: A comprehensive meta-analysis of five randomised controlled trials","volume":"400","author":"Vaduganathan","year":"2022","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s12933-020-01105-5","article-title":"SGLT2 inhibitors and atrial fibrillation in type 2 diabetes: A systematic review with meta-analysis of 16 randomized controlled trials","volume":"19","author":"Li","year":"2020","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Muszy\u0144ski, P., and Bonda, T.A. (2021). Mitochondrial Dysfunction in Atrial Fibrillation\u2014Mechanisms and Pharmacological Interventions. J. Clin. Med., 10.","DOI":"10.3390\/jcm10112385"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Karamichalakis, N., Kolovos, V., Paraskevaidis, I., and Tsougos, E. (2022). A New Hope: Sodium-Glucose Cotransporter-2 Inhibition to Prevent Atrial Fibrillation. J. Cardiovasc. Dev. Dis., 9.","DOI":"10.3390\/jcdd9080236"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kolesnik, E., Scherr, D., Rohrer, U., Benedikt, M., Manninger, M., Sourij, H., and von Lewinski, D. (2022). SGLT2 Inhibitors and Their Antiarrhythmic Properties. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031678"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s12933-019-0964-4","article-title":"Empagliflozin, a sodium glucose co-transporter-2 inhibitor, alleviates atrial remodeling and improves mitochondrial function in high-fat diet\/streptozotocin-induced diabetic rats","volume":"18","author":"Shao","year":"2019","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1152\/japplphysiol.01000.2014","article-title":"Rapidly elevated levels of PGC-1\u03b1-b protein in human skeletal muscle after exercise: Exploring regulatory factors in a randomized controlled trial","volume":"119","author":"Gidlund","year":"2015","journal-title":"J. Appl. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1074\/jbc.M606116200","article-title":"Exercise-induced Mitochondrial Biogenesis Begins before the Increase in Muscle PGC-1\u03b1; Expression","volume":"282","author":"Wright","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1057\/jt.2009.5","article-title":"The correlation coefficient: Its values range between +1\/\u22121, or do they?","volume":"17","author":"Ratner","year":"2009","journal-title":"J. Target. Meas. Anal. Mark."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1002\/ejhf.1663","article-title":"Efficacy of empagliflozin on heart failure and renal outcomes in patients with atrial fibrillation: Data from the EMPA-REG OUTCOME trial","volume":"22","author":"Slawik","year":"2020","journal-title":"Eur. J. Heart Fail."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1093\/eurjpc\/zwad356","article-title":"SGLT2 inhibitors for the prevention of atrial fibrillation: A systemic review and meta-analysis","volume":"31","author":"Zhang","year":"2023","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.21037\/jtd-22-550","article-title":"The effectiveness of SGLT2 inhibitor in the incidence of atrial fibrillation\/atrial flutter in patients with type 2 diabetes mellitus\/heart failure: A systematic review and meta-analysis","volume":"14","author":"Wang","year":"2022","journal-title":"J. Thorac. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Radlinger, B., Hornsteiner, F., Folie, S., Salvenmoser, W., Haubner, B.J., Schuetz, T., Haas, S., Ress, C., Adolph, T.E., and Salzmann, K. (2020). Cardioprotective effects of short-term empagliflozin treatment in db\/db mice. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-76698-8"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1186\/s12933-021-01392-6","article-title":"Empagliflozin protects the heart against ischemia\/reperfusion-induced sudden cardiac death","volume":"20","author":"Hu","year":"2021","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e024478","DOI":"10.1161\/JAHA.121.024478","article-title":"Disruption of Sarcoplasmic Reticulum-Mitochondrial Contacts Underlies Contractile Dysfunction in Experimental and Human Atrial Fibrillation: A Key Role of Mitofusin 2","volume":"11","author":"Li","year":"2022","journal-title":"J. Am. Heart Assoc."},{"key":"ref_22","first-page":"53","article-title":"Sodium-glucose cotransporter 2 inhibitors and mitochondrial functions: State of the art","volume":"22","author":"Yaribeygi","year":"2023","journal-title":"EXCLI J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e84235","DOI":"10.7554\/eLife.84235","article-title":"A human mitofusin 2 mutation can cause mitophagic cardiomyopathy","volume":"12","author":"Franco","year":"2023","journal-title":"Elife"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.cjca.2019.08.033","article-title":"Direct Effects of Empagliflozin on Extracellular Matrix Remodelling in Human Cardiac Myofibroblasts: Novel Translational Clues to Explain EMPA-REG OUTCOME Results","volume":"36","author":"Kang","year":"2020","journal-title":"Can. J. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"119440","DOI":"10.1016\/j.lfs.2021.119440","article-title":"Anti-arrhythmic and inotropic effects of empagliflozin following myocardial ischemia","volume":"276","author":"Azam","year":"2021","journal-title":"Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1007\/s00125-017-4509-7","article-title":"Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: Inhibition of Na+\/H+ exchanger, lowering of cytosolic Na+ and vasodilation","volume":"61","author":"Uthman","year":"2018","journal-title":"Diabetologia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"ehac544.508","DOI":"10.1093\/eurheartj\/ehac544.508","article-title":"Impact of diabetes and glucose-lowering therapy on post-operative atrial fibrillation after cardiac surgery: Secondary analysis of the SEARCH-AF CardioLink-1 randomized clinical trial","volume":"43","author":"Pandey","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"20200502","DOI":"10.4022\/jafib.20200502","article-title":"Effect of SLGT2 Inhibitors on Patients with Atrial Fibrillation","volume":"14","author":"Haloot","year":"2021","journal-title":"J. Atr. Fibrillation"},{"key":"ref_29","first-page":"1","article-title":"Empagliflozin in paroxysmal or persistent atrial fibrillation: A possible antiarrhythmic effect","volume":"7","author":"Fazio","year":"2021","journal-title":"Diabetes Updates"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Proietti, R., Rivera-Caravaca, J.M., L\u00f3pez-G\u00e1lvez, R., Harrison, S.L., Mar\u00edn, F., Underhill, P., Shantsila, E., McDowell, G., Vinciguerra, M., and Davies, R. (2023). Cerebrovascular, Cognitive and Cardiac Benefits of SGLT2 Inhibitors Therapy in Patients with Atrial Fibrillation and Type 2 Diabetes Mellitus: Results from a Global Federated Health Network Analysis. J. Clin. Med., 12.","DOI":"10.3390\/jcm12082814"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s40262-013-0126-x","article-title":"Pharmacokinetic and pharmacodynamic profile of empagliflozin, a sodium glucose co-transporter 2 inhibitor","volume":"53","author":"Scheen","year":"2014","journal-title":"Clin. Pharmacokinet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1161\/CIRCRESAHA.120.316366","article-title":"Animal Models of Atrial Fibrillation","volume":"127","author":"Bapat","year":"2020","journal-title":"Circ. Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wang, C.-Y., Chen, C.-C., Lin, M.-H., Su, H.-T., Ho, M.-Y., Yeh, J.-K., Tsai, M.-L., Hsieh, I.-C., and Wen, M.-S. (2020). TLR9 Binding to Beclin 1 and Mitochondrial SIRT3 by a Sodium-Glucose Co-Transporter 2 Inhibitor Protects the Heart from Doxorubicin Toxicity. Biology, 9.","DOI":"10.3390\/biology9110369"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.freeradbiomed.2010.04.015","article-title":"Up-regulation of heme oxygenase-1 expression through CaMKII-ERK1\/2-Nrf2 signaling mediates the anti-inflammatory effect of bisdemethoxycurcumin in LPS-stimulated macrophages","volume":"49","author":"Kim","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"E145","DOI":"10.1152\/ajpendo.00755.2009","article-title":"PGC-1alpha regulation by exercise training and its influences on muscle function and insulin sensitivity","volume":"299","author":"Lira","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"172810","DOI":"10.1016\/j.ejphar.2019.172810","article-title":"Empagliflozin restores lowered exercise endurance capacity via the activation of skeletal muscle fatty acid oxidation in a murine model of heart failure","volume":"866","author":"Nambu","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"H117","DOI":"10.1152\/ajpheart.00100.2021","article-title":"Treatments for skeletal muscle abnormalities in heart failure: Sodium-glucose transporter 2 and ketone bodies","volume":"322","author":"Takada","year":"2022","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1007\/s11357-022-00563-x","article-title":"SGLT2 inhibition attenuates arterial dysfunction and decreases vascular F-actin content and expression of proteins associated with oxidative stress in aged mice","volume":"44","author":"Soares","year":"2022","journal-title":"Geroscience"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Koizumi, T., Watanabe, M., Yokota, T., Tsuda, M., Handa, H., Koya, J., Nishino, K., Tatsuta, D., Natsui, H., and Kadosaka, T. (2023). Empagliflozin suppresses mitochondrial reactive oxygen species generation and mitigates the inducibility of atrial fibrillation in diabetic rats. Front. Cardiovasc. Med., 10.","DOI":"10.3389\/fcvm.2023.1005408"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"175194","DOI":"10.1016\/j.ejphar.2022.175194","article-title":"Empagliflozin improves cardiac mitochondrial function and survival through energy regulation in a murine model of heart failure","volume":"931","author":"Shiraki","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Seefeldt, J.M., Lassen, T.R., Hjortbak, M.V., Jespersen, N.R., Kvist, F., Hansen, J., and B\u00f8tker, H.E. (2021). Cardioprotective effects of empagliflozin after ischemia and reperfusion in rats. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-89149-9"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/nprot.2006.478","article-title":"Organelle isolation: Functional mitochondria from mouse liver, muscle and cultured filroblasts","volume":"2","author":"Frezza","year":"2007","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/4\/1664\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:35:10Z","timestamp":1760027710000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/4\/1664"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,15]]},"references-count":42,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["ijms26041664"],"URL":"https:\/\/doi.org\/10.3390\/ijms26041664","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,15]]}}}