{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T05:01:17Z","timestamp":1791435677587,"version":"4.3.3"},"reference-count":66,"publisher":"American Society for Clinical Investigation","issue":"20","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,10,18]]},"abstract":"<jats:p>Patients with diabetes are at significantly higher risk of developing heart failure. Increases in advanced glycation end products are a proposed pathophysiological link, but their impact and mechanism remain incompletely understood. Methylglyoxal (MG) is a glycolysis byproduct, elevated in diabetes, and modifies arginine and lysine residues. We show that left ventricular myofilament from patients with diabetes and heart failure (dbHF) exhibited increased MG modifications compared with nonfailing controls (NF) or heart failure patients without diabetes. In skinned NF human and mouse cardiomyocytes, acute MG treatment depressed both calcium sensitivity and maximal calcium-activated force in a dose-dependent manner. Importantly, dbHF myocytes were resistant to myofilament functional changes from MG treatment, indicating that myofilaments from dbHF patients already had depressed function arising from MG modifications. In human dbHF and MG-treated mice, mass spectrometry identified increased MG modifications on actin and myosin. Cosedimentation and in vitro motility assays indicate that MG modifications on actin and myosin independently depress calcium sensitivity, and mechanistically, the functional consequence requires actin\/myosin interaction with thin-filament regulatory proteins. MG modification of the myofilament may represent a critical mechanism by which diabetes induces heart failure, as well as a therapeutic target to avoid the development of or ameliorate heart failure in these patients.<\/jats:p>","DOI":"10.1172\/jci.insight.121264","type":"journal-article","created":{"date-parts":[[2018,10,17]],"date-time":"2018-10-17T11:01:49Z","timestamp":1539774109000},"source":"Crossref","is-referenced-by-count":72,"title":["Diabetes with heart failure increases methylglyoxal modifications in the sarcomere, which inhibit function"],"prefix":"10.1172","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8903-7085","authenticated-orcid":true,"given":"Maria","family":"Papadaki","sequence":"first","affiliation":[{"name":"Loyola University Chicago, Department of Cell and Molecular Physiology, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald J.","family":"Holewinski","sequence":"additional","affiliation":[{"name":"Cedars-Sinai Medical Center, Heart Institute, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha Beck","family":"Previs","sequence":"additional","affiliation":[{"name":"University of Vermont, Department of Molecular Physiology and Biophysics, Burlington, Vermont, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Martin","sequence":"additional","affiliation":[{"name":"Loyola University Chicago, Department of Cell and Molecular Physiology, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa J.","family":"Stachowski","sequence":"additional","affiliation":[{"name":"Loyola University Chicago, Department of Cell and Molecular Physiology, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Li","sequence":"additional","affiliation":[{"name":"University of Vermont, Department of Molecular Physiology and Biophysics, Burlington, Vermont, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheavar A.","family":"Blair","sequence":"additional","affiliation":[{"name":"University of Kentucky, Department of Physiology, Lexington, Kentucky, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine S.","family":"Moravec","sequence":"additional","affiliation":[{"name":"The Cleveland Clinic, Department of Molecular Cardiology, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Van Eyk","sequence":"additional","affiliation":[{"name":"Cedars-Sinai Medical Center, Heart Institute, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth S.","family":"Campbell","sequence":"additional","affiliation":[{"name":"University of Kentucky, Department of Physiology, Lexington, Kentucky, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Warshaw","sequence":"additional","affiliation":[{"name":"University of Vermont, Department of Molecular Physiology and Biophysics, Burlington, Vermont, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Kirk","sequence":"additional","affiliation":[{"name":"Loyola University Chicago, Department of Cell and Molecular Physiology, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2018,10,18]]},"reference":[{"key":"B1","unstructured":"National Diabetes Statistics Report, 2017. Centers for Disease Control and Prevention. https:\/\/www.cdc.gov\/diabetes\/pdfs\/data\/statistics\/national-diabetes-statistics-report.pdf Accessed September 17, 2018"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.21.7.1138"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9149(74)90089-7"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.306923"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2012.07.027"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nature04250"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1177\/0269881113495596"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1042\/BST20140018"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/0098-2997(93)90002-U"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/0168-8227(89)90101-0"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2010.04.004"},{"issue":"3","key":"B12","doi-asserted-by":"crossref","DOI":"10.3390\/ijms18030480","article-title":"Intracellular accumulation of methylglyoxal by glyoxalase 1 knock down alters collagen homoeostasis in L6 myoblasts","volume":"18","author":"Stratmann","year":"2017","journal-title":"Int J Mol Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-017-0646-x"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311586"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.05.016"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.2337\/db10-1145"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1124\/mol.112.078352"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-013-9384-9"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2013.11.011"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2010.03.024"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00638.2005"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00049.2004"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200605000-00014"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-005-5254-4"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12058"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/science.1200113"},{"issue":"Pt 3","key":"B27","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1042\/bj20030763","article-title":"Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spectrometry","volume":"375","author":"Thornalley","year":"2003","journal-title":"Biochem J"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-010-0783-0"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-012-9313-3"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.013215"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.312166"},{"issue":"Pt 1","key":"B32","first-page":"1","article-title":"Assay of advanced glycation endproducts (AGEs): surveying AGEs by chromatographic assay with derivatization by 6-aminoquinolyl-N-hydroxysuccinimidyl-carbamate and application to Nepsilon-carboxymethyl-lysine- and Nepsilon-(1-carboxyethyl)lysine-modified albumin","volume":"364","author":"Ahmed","year":"2002","journal-title":"Biochem J"},{"issue":"1","key":"B33","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.1400205","article-title":"Myosin-binding protein C corrects an intrinsic inhomogeneity in cardiac excitation-contraction coupling","volume":"1","author":"Previs","year":"2015","journal-title":"Sci Adv"},{"issue":"2","key":"B34","doi-asserted-by":"crossref","first-page":"147","DOI":"10.33549\/physiolres.931585","article-title":"Glycotoxines, carbonyl stress and relevance to diabetes and its complications","volume":"59","author":"Turk","year":"2010","journal-title":"Physiol Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.205427"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1126\/science.287.5452.488"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.5b00380"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1021\/bi010893n"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2013.01.037"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2000.80.2.853"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2017.10.004"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.08.070"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1003604107"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2004.1566"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.05.037"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2013.10.002"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.1996.0180"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.109.912345"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00922.2008"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.48.1.198"},{"issue":"11\u201312","key":"B51","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1016\/j.jchromb.2009.02.055","article-title":"Methylglyoxal, protein binding and biological samples: are we getting the true measure?","volume":"877","author":"Dhar","year":"2009","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2011.02.015"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs259"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00215.2010"},{"issue":"3","key":"B55","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1093\/cvr\/cvn289","article-title":"Build it up-tear it down: protein quality control in the cardiac sarcomere","volume":"81","author":"Willis","year":"2009","journal-title":"Cardiovasc Res"},{"issue":"20","key":"B56","doi-asserted-by":"crossref","DOI":"10.14814\/phy2.13462","article-title":"Abundance, localization, and functional correlates of the advanced glycation end-product carboxymethyl lysine in human myocardium","volume":"5","author":"LeWinter","year":"2017","journal-title":"Physiol Rep"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.186809"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1172\/JCI69253"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad2899"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.numecd.2013.01.005"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1161\/hc3801.097806"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.2165\/11315260-000000000-00000"},{"issue":"1","key":"B63","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S0022-3565(24)36366-9","article-title":"Ca++ sensitizers impair cardiac relaxation in failing human myocardium","volume":"280","author":"Hajjar","year":"1997","journal-title":"J Pharmacol Exp Ther"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvv181"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1316001111"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2003.10.006"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/121264\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:39:28Z","timestamp":1779194368000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/121264"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,18]]},"references-count":66,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2018,10,18]]},"published-print":{"date-parts":[[2018,10,18]]}},"alternative-id":["10.1172\/jci.insight.121264"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.121264","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,18]]},"article-number":"e121264"}}