{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:23:42Z","timestamp":1787239422662,"version":"build-2736575974"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,9,3]],"date-time":"2019-09-03T00:00:00Z","timestamp":1567468800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,9,3]],"date-time":"2019-09-03T00:00:00Z","timestamp":1567468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Sex disparities modulate cardiac function, although the proteins and mechanisms remain to be elucidated. We recently demonstrated a mosaic pattern of protein expression in the heart for over 100 proteins. Here we investigate one of these proteins, myosin light chain 4 (MYL4), which is important for contractile functions by increasing force production. We assayed the expression pattern of MYL4 across 756 ventricular myocardial samples from 668 individuals utilizing a semi-automated Cell Profiler method on five tissue microarrays (TMAs) of cardiac tissues across a diverse set of diseases. The percentage of MYL4 positive cells was significantly higher in male subjects independently across all five TMAs, regardless of disease state (p\u2009=\u20098.66e-15). Higher MYL4 expression was also modestly associated with hypertrophic cardiomyopathy (p\u2009=\u20096.3e-04). MYL4 expression did not associate with sudden cardiac death or other cardiomyopathies. This study demonstrates a new mosaic pattern of protein expression that underlies sex disparities in the human heart.<\/jats:p>","DOI":"10.1038\/s41598-019-49191-0","type":"journal-article","created":{"date-parts":[[2019,9,3]],"date-time":"2019-09-03T06:08:04Z","timestamp":1567490884000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Human cardiac myosin light chain 4 (MYL4) mosaic expression patterns vary by sex"],"prefix":"10.1038","volume":"9","author":[{"given":"Tony Y.","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan E.","family":"Arking","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J.","family":"Maleszewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Fox-Talbot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim O.","family":"Nieuwenhuis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lakshmi","family":"Santhanam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renu","family":"Virmani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2356-950X","authenticated-orcid":false,"given":"Avi Z.","family":"Rosenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7112-7389","authenticated-orcid":false,"given":"Marc K.","family":"Halushka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,9,3]]},"reference":[{"key":"49191_CR1","doi-asserted-by":"publisher","first-page":"2735","DOI":"10.1016\/j.lfs.2004.12.013","volume":"76","author":"SH Chu","year":"2005","unstructured":"Chu, S. H. et al. Sex differences in expression of calcium-handling proteins and beta-adrenergic receptors in rat heart ventricle. Life sciences 76, 2735\u20132749, https:\/\/doi.org\/10.1016\/j.lfs.2004.12.013 (2005).","journal-title":"Life sciences"},{"key":"49191_CR2","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1007\/BF01906669","volume":"78","author":"JM Capasso","year":"1983","unstructured":"Capasso, J. M., Remily, R. M., Smith, R. H. & Sonnenblick, E. H. Sex differences in myocardial contractility in the rat. Basic research in cardiology 78, 156\u2013171 (1983).","journal-title":"Basic research in cardiology"},{"key":"49191_CR3","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/S0024-3205(99)00623-2","volume":"66","author":"J Wattanapermpool","year":"2000","unstructured":"Wattanapermpool, J., Riabroy, T. & Preawnim, S. Estrogen supplement prevents the calcium hypersensitivity of cardiac myofilaments in ovariectomized rats. Life sciences 66, 533\u2013543 (2000).","journal-title":"Life sciences"},{"key":"49191_CR4","doi-asserted-by":"publisher","first-page":"77","DOI":"10.2217\/whe.09.80","volume":"6","author":"P Bhupathy","year":"2010","unstructured":"Bhupathy, P., Haines, C. D. & Leinwand, L. A. Influence of sex hormones and phytoestrogens on heart disease in men and women. Women\u2019s health 6, 77\u201395, https:\/\/doi.org\/10.2217\/whe.09.80 (2010).","journal-title":"Women\u2019s health"},{"key":"49191_CR5","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1210\/en.2003-0816","volume":"145","author":"Y Li","year":"2004","unstructured":"Li, Y. et al. Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A. Endocrinology 145, 951\u2013958, https:\/\/doi.org\/10.1210\/en.2003-0816 (2004).","journal-title":"Endocrinology"},{"key":"49191_CR6","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1042\/cs1010447","volume":"101","author":"S Maffei","year":"2001","unstructured":"Maffei, S., Del Ry, S., Prontera, C. & Clerico, A. Increase in circulating levels of cardiac natriuretic peptides after hormone replacement therapy in postmenopausal women. Clinical science 101, 447\u2013453 (2001).","journal-title":"Clinical science"},{"key":"49191_CR7","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1056\/NEJM199307223290406","volume":"329","author":"NK Wenger","year":"1993","unstructured":"Wenger, N. K., Speroff, L. & Packard, B. Cardiovascular health and disease in women. The New England journal of medicine 329, 247\u2013256, https:\/\/doi.org\/10.1056\/NEJM199307223290406 (1993).","journal-title":"The New England journal of medicine"},{"key":"49191_CR8","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/S0735-1097(99)00165-5","volume":"34","author":"EO Weinberg","year":"1999","unstructured":"Weinberg, E. O. et al. Gender differences in molecular remodeling in pressure overload hypertrophy. Journal of the American College of Cardiology 34, 264\u2013273 (1999).","journal-title":"Journal of the American College of Cardiology"},{"key":"49191_CR9","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1152\/physiolgenomics.00265.2007","volume":"33","author":"GE Haddad","year":"2008","unstructured":"Haddad, G. E. et al. Human cardiac-specific cDNA array for idiopathic dilated cardiomyopathy: sex-related differences. Physiological genomics 33, 267\u2013277, https:\/\/doi.org\/10.1152\/physiolgenomics.00265.2007 (2008).","journal-title":"Physiological genomics"},{"key":"49191_CR10","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/S0008-6363(97)00258-7","volume":"37","author":"MC Schaub","year":"1998","unstructured":"Schaub, M. C., Hefti, M. A., Zuellig, R. A. & Morano, I. Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms. Cardiovasc Res 37, 381\u2013404 (1998).","journal-title":"Cardiovasc Res"},{"key":"49191_CR11","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.carpath.2018.03.002","volume":"34","author":"TY Wang","year":"2018","unstructured":"Wang, T. Y. et al. Cardiomyocytes have mosaic patterns of protein expression. Cardiovasc Pathol 34, 50\u201357, https:\/\/doi.org\/10.1016\/j.carpath.2018.03.002 (2018).","journal-title":"Cardiovasc Pathol"},{"key":"49191_CR12","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1172\/JCI111466","volume":"74","author":"H Tsuchimochi","year":"1984","unstructured":"Tsuchimochi, H. et al. Isozymic changes in myosin of human atrial myocardium induced by overload. Immunohistochemical study using monoclonal antibodies. The Journal of clinical investigation 74, 662\u2013665, https:\/\/doi.org\/10.1172\/JCI111466 (1984).","journal-title":"The Journal of clinical investigation"},{"key":"49191_CR13","first-page":"151","volume":"7","author":"O Ritter","year":"2002","unstructured":"Ritter, O., Bottez, N., Burkard, N., Schulte, H. D. & Neyses, L. A molecular mechanism improving the contractile state in human myocardial hypertrophy. Experimental and clinical cardiology 7, 151\u2013157 (2002).","journal-title":"Experimental and clinical cardiology"},{"key":"49191_CR14","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1007\/s001099900030","volume":"77","author":"O Ritter","year":"1999","unstructured":"Ritter, O. et al. Expression of atrial myosin light chains but not alpha-myosin heavy chains is correlated in vivo with increased ventricular function in patients with hypertrophic obstructive cardiomyopathy. Journal of molecular medicine 77, 677\u2013685 (1999).","journal-title":"Journal of molecular medicine"},{"key":"49191_CR15","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1006\/jmcc.1996.0353","volume":"29","author":"I Morano","year":"1997","unstructured":"Morano, I. et al. Changes in essential myosin light chain isoform expression provide a molecular basis for isometric force regulation in the failing human heart. Journal of molecular and cellular cardiology 29, 1177\u20131187, https:\/\/doi.org\/10.1006\/jmcc.1996.0353 (1997).","journal-title":"Journal of molecular and cellular cardiology"},{"key":"49191_CR16","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1161\/01.RES.70.5.1035","volume":"70","author":"G Sutsch","year":"1992","unstructured":"Sutsch, G. et al. Hemodynamic performance and myosin light chain-1 expression of the hypertrophied left ventricle in aortic valve disease before and after valve replacement. Circ Res 70, 1035\u20131043 (1992).","journal-title":"Circ Res"},{"key":"49191_CR17","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1172\/JCI118813","volume":"98","author":"M Morano","year":"1996","unstructured":"Morano, M. et al. Regulation of human heart contractility by essential myosin light chain isoforms. The Journal of clinical investigation 98, 467\u2013473, https:\/\/doi.org\/10.1172\/JCI118813 (1996).","journal-title":"The Journal of clinical investigation"},{"key":"49191_CR18","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1016\/j.cell.2018.01.029","volume":"172","author":"SA Lambert","year":"2018","unstructured":"Lambert, S. A. et al. The Human Transcription Factors. Cell 172, 650\u2013665, https:\/\/doi.org\/10.1016\/j.cell.2018.01.029 (2018).","journal-title":"Cell"},{"key":"49191_CR19","doi-asserted-by":"publisher","first-page":"e23506","DOI":"10.1371\/journal.pone.0023506","volume":"6","author":"Y Zhang","year":"2011","unstructured":"Zhang, Y. et al. Transcriptional profiling of human liver identifies sex-biased genes associated with polygenic dyslipidemia and coronary artery disease. PLoS One 6, e23506, https:\/\/doi.org\/10.1371\/journal.pone.0023506 (2011).","journal-title":"PLoS One"},{"key":"49191_CR20","doi-asserted-by":"publisher","first-page":"12215","DOI":"10.1074\/jbc.272.18.12215","volume":"272","author":"YF Lee","year":"1997","unstructured":"Lee, Y. F., Pan, H. J., Burbach, J. P., Morkin, E. & Chang, C. Identification of direct repeat 4 as a positive regulatory element for the human TR4 orphan receptor. A modulator for the thyroid hormone target genes. J Biol Chem 272, 12215\u201312220 (1997).","journal-title":"J Biol Chem"},{"key":"49191_CR21","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.devcel.2013.04.017","volume":"25","author":"SP Wu","year":"2013","unstructured":"Wu, S. P. et al. Atrial identity is determined by a COUP-TFII regulatory network. Developmental cell 25, 417\u2013426, https:\/\/doi.org\/10.1016\/j.devcel.2013.04.017 (2013).","journal-title":"Developmental cell"},{"key":"49191_CR22","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1161\/CIRCGENETICS.108.802652","volume":"1","author":"DR Fermin","year":"2008","unstructured":"Fermin, D. R. et al. Sex and age dimorphism of myocardial gene expression in nonischemic human heart failure. Circulation. Cardiovascular genetics 1, 117\u2013125, https:\/\/doi.org\/10.1161\/CIRCGENETICS.108.802652 (2008).","journal-title":"Circulation. Cardiovascular genetics"},{"key":"49191_CR23","doi-asserted-by":"publisher","first-page":"H946","DOI":"10.1152\/ajpheart.00822.2012","volume":"304","author":"C Chu","year":"2013","unstructured":"Chu, C. et al. Intraventricular and interventricular cellular heterogeneity of inotropic responses to alpha(1)-adrenergic stimulation. Am J Physiol Heart Circ Physiol 304, H946\u2013953, https:\/\/doi.org\/10.1152\/ajpheart.00822.2012 (2013).","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"49191_CR24","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-13-26","volume":"13","author":"S Gupta","year":"2012","unstructured":"Gupta, S., Halushka, M. K., Hilton, G. M. & Arking, D. E. Postmortem cardiac tissue maintains gene expression profile even after late harvesting. BMC Genomics 13, 26, https:\/\/doi.org\/10.1186\/1471-2164-13-26 (2012).","journal-title":"BMC Genomics"},{"key":"49191_CR25","doi-asserted-by":"publisher","first-page":"3961","DOI":"10.1093\/eurheartj\/ehy474","volume":"39","author":"FN Ashar","year":"2018","unstructured":"Ashar, F. N. et al. A comprehensive evaluation of the genetic architecture of sudden cardiac arrest. European heart journal 39, 3961\u20133969, https:\/\/doi.org\/10.1093\/eurheartj\/ehy474 (2018).","journal-title":"European heart journal"},{"key":"49191_CR26","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1093\/bioinformatics\/btr095","volume":"27","author":"L Kamentsky","year":"2011","unstructured":"Kamentsky, L. et al. Improved structure, function and compatibility for CellProfiler: modular high-throughput image analysis software. Bioinformatics 27, 1179\u20131180, https:\/\/doi.org\/10.1093\/bioinformatics\/btr095 (2011).","journal-title":"Bioinformatics"},{"key":"49191_CR27","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","volume":"9","author":"CA Schneider","year":"2012","unstructured":"Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH Image to ImageJ: 25 years of image analysis. Nature methods 9, 671\u2013675 (2012).","journal-title":"Nature methods"},{"key":"49191_CR28","doi-asserted-by":"publisher","unstructured":"Fishilevich, S. et al. GeneHancer: genome-wide integration of enhancers and target genes in GeneCards. Database: the journal of biological databases and curation 2017, https:\/\/doi.org\/10.1093\/database\/bax028 (2017).","DOI":"10.1093\/database\/bax028"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49191-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49191-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49191-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T08:14:17Z","timestamp":1671264857000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49191-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,3]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["49191"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-49191-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,3]]},"assertion":[{"value":"16 May 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 August 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 September 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"12681"}}