{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:16:42Z","timestamp":1790705802394,"version":"4.1.0"},"reference-count":103,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T00:00:00Z","timestamp":1723593600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Arrhythmogenic cardiomyopathy (AC) is a familial cardiac disease, mainly caused by mutations in desmosomal genes, which accounts for most cases of stress\u2010related arrhythmic sudden death, in young and athletes. AC hearts display fibro\u2010fatty lesions that generate the arrhythmic substrate and cause contractile dysfunction. A correlation between physical\/emotional stresses and arrhythmias supports the involvement of sympathetic neurons (SNs) in the disease, but this has not been confirmed previously. Here, we combined molecular, <jats:italic>in vitro<\/jats:italic> and <jats:italic>ex vivo<\/jats:italic> analyses to determine the role of AC\u2010linked DSG2 downregulation on SN biology and assess cardiac sympathetic innervation in desmoglein\u20102\u00a0mutant (<jats:italic>Dsg2<jats:sup>mut\/mut<\/jats:sup><\/jats:italic>) mice. Molecular assays showed that SNs express DSG2, implying that DSG2\u2010mutation carriers would harbour the mutant protein in SNs. Confocal immunofluorescence of heart sections and 3\u2010D reconstruction of SN network in clarified heart blocks revealed significant changes in the physiologialc SN topology, with massive hyperinnervation of the intact subepicardial layers and heterogeneous distribution of neurons in fibrotic areas. Cardiac SNs isolated from <jats:italic>Dsg2<jats:sup>mut\/mut<\/jats:sup><\/jats:italic> neonatal mice, prior to the establishment of cardiac innervation, show alterations in axonal sprouting, process development and distribution of varicosities. Consistently, virus\u2010assisted DSG2 downregulation replicated, in PC12\u2010derived SNs, the phenotypic alterations displayed by <jats:italic>Dsg2<jats:sup>mut\/mut<\/jats:sup><\/jats:italic> primary neurons, corroborating that AC\u2010linked <jats:italic>Dsg2<\/jats:italic> variants may affect SNs. Our results reveal that altered sympathetic innervation is an unrecognized feature of AC hearts, which may result from the combination of cell\u2010autonomous and context\u2010dependent factors implicated in myocardial remodelling. Our results favour the concept that AC is a disease of multiple cell types also hitting cardiac SNs.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16221-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Arrhythmogenic cardiomyopathy is a genetically determined cardiac disease, which accounts for most cases of stress\u2010related arrhythmic sudden death.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Arrhythmogenic cardiomyopathy linked to mutations in desmoglein\u20102 (DSG2) is frequent and leads to a left\u2010dominant form of the disease.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Arrhythmogenic cardiomyopathy has been approached thus far as a disease of cardiomyocytes, but we here unveil that DSG2 is expressed, in addition to cardiomyocytes, by cardiac and extracardiac sympathetic neurons, although not organized into desmosomes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>AC\u2010linked DSG2 downregulation primarily affect sympathetic neurons, resulting in the significant increase in cardiac innervation density, accompanied by alterations in sympathetic neuron distribution.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our data supports the notion that AC develops with the contribution of several \u2018desmosomal protein\u2010carrying\u2019 cell types and systems.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp286845","type":"journal-article","created":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T19:03:51Z","timestamp":1723662231000},"page":"1959-1982","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Cardiac sympathetic neurons are additional cells affected in genetically determined arrhythmogenic cardiomyopathy"],"prefix":"10.1113","volume":"603","author":[{"given":"Induja Perumal","family":"Vanaja","sequence":"first","affiliation":[{"name":"Department of Cardiac, Thoracic, Vascular Sciences and Public Health University of Padova  Padova Italy"},{"name":"Veneto Institute of Molecular Medicine (VIMM)  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Scalco","sequence":"additional","affiliation":[{"name":"Veneto Institute of Molecular Medicine (VIMM)  Padova Italy"},{"name":"Department of Biomedical Sciences University of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Ronfini","sequence":"additional","affiliation":[{"name":"Veneto Institute of Molecular Medicine (VIMM)  Padova Italy"},{"name":"Department of Biomedical Sciences University of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Di","family":"Bona","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, Vascular Sciences and Public Health University of Padova  Padova Italy"},{"name":"Veneto Institute of Molecular Medicine (VIMM)  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Olianti","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology (IFC) National Research Council  Florence Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Rizzo","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, Vascular Sciences and Public Health University of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen P.","family":"Chelko","sequence":"additional","affiliation":[{"name":"Department of Medicine Johns Hopkins University, School of Medicine  Baltimore MD USA"},{"name":"Department of Biomedical Sciences Florida State University, College of Medicine  Tallahassee FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Corrado","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, Vascular Sciences and Public Health University of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Sacconi","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology (IFC) National Research Council  Florence Florence Italy"},{"name":"Institute for Experimental Cardiovascular Medicine University Heart Center and Medical Faculty, University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Basso","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, Vascular Sciences and Public Health University of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Mongillo","sequence":"additional","affiliation":[{"name":"Veneto Institute of Molecular Medicine (VIMM)  Padova Italy"},{"name":"Department of Biomedical Sciences University of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Zaglia","sequence":"additional","affiliation":[{"name":"Veneto Institute of Molecular Medicine (VIMM)  Padova Italy"},{"name":"Department of Biomedical Sciences University of Padova  Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,14]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9123804"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-021-01105-7"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.3109\/15419061.2013.876016"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3008008"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2015.04.012"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60256-7"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2011.173"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.06.043"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00380-006-0963-8"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-014-2015-5"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs218"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2014.02.001"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00127-0"},{"issue":"5","key":"e_1_2_5_15_1","article-title":"Central role for GSK3\u03b2 in the pathogenesis of arrhythmogenic cardiomyopathy","volume":"1","author":"Chelko S. P.","year":"2016","journal-title":"Journal of Clinical Investigation Insight"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrcr.2021.07.010"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes14101864"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2481"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(97)00332-X"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(01)00254-1"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2003.03.002"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.104.486977"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.296.13.1593"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.913871"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv183"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1509267"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1177\/2047487318805584"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1136\/bjsports-2018-100529"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep09808"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-20450-w"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.113.001224"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2016.08.004"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP282828"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2016.01.009"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.115.001359"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq353"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1461"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.3791\/62795"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvy057"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP271840"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP284739"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-019-0221-2"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2004.08.068"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1570"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201710161"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.114.000974"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.039710"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.257253"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abf2750"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep38898"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01025-10"},{"issue":"1","key":"e_1_2_5_53_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1023\/A:1009714718034","article-title":"Arrhythmogenic right ventricular dysplasia: Clinical results with implantable cardioverter defibrillators","volume":"1","author":"Link M. S.","year":"1997","journal-title":"Journal of Interventional Cardiac Electrophysiology: An International Journal of Arrhythmias and Pacing"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.196899"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.255075"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt508"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00295.2015"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.3109\/15419061.2011.621561"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.09.951"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)02379-5"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.111.974881"},{"key":"e_1_2_5_62_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw213"},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvae088.098"},{"key":"e_1_2_5_64_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.262345"},{"key":"e_1_2_5_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-71174-9"},{"key":"e_1_2_5_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2021.07.012"},{"key":"e_1_2_5_67_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.154252"},{"key":"e_1_2_5_68_1","doi-asserted-by":"publisher","DOI":"10.3109\/15419061.2014.906533"},{"key":"e_1_2_5_69_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP276200"},{"key":"e_1_2_5_70_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.583674"},{"key":"e_1_2_5_71_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20090641"},{"key":"e_1_2_5_72_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.110.959031"},{"key":"e_1_2_5_73_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-016-0407-1"},{"key":"e_1_2_5_74_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP275693"},{"key":"e_1_2_5_75_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv316"},{"key":"e_1_2_5_76_1","doi-asserted-by":"publisher","DOI":"10.1086\/344208"},{"key":"e_1_2_5_77_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.113.000338"},{"key":"e_1_2_5_78_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2023.1191965"},{"key":"e_1_2_5_79_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2015.12.015"},{"key":"e_1_2_5_80_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs219"},{"key":"e_1_2_5_81_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.181"},{"key":"e_1_2_5_82_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10091871"},{"key":"e_1_2_5_83_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_2_5_84_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.309631"},{"key":"e_1_2_5_85_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0039584"},{"key":"e_1_2_5_86_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv579"},{"key":"e_1_2_5_87_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2021.08.015"},{"key":"e_1_2_5_88_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11193049"},{"key":"e_1_2_5_89_1","doi-asserted-by":"publisher","DOI":"10.1086\/509122"},{"key":"e_1_2_5_90_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198801213180301"},{"key":"e_1_2_5_91_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.3.189"},{"key":"e_1_2_5_92_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibtech.2023.08.007"},{"key":"e_1_2_5_93_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24032109"},{"key":"e_1_2_5_94_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvaa084"},{"key":"e_1_2_5_95_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurjhf\/hfs119"},{"key":"e_1_2_5_96_1","doi-asserted-by":"publisher","DOI":"10.1117\/1.JBO.17.6.060901"},{"key":"e_1_2_5_97_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.101.13.1552"},{"key":"e_1_2_5_98_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000121738.88273.43"},{"key":"e_1_2_5_99_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs320"},{"key":"e_1_2_5_100_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI66339"},{"key":"e_1_2_5_101_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00418-016-1456-1"},{"key":"e_1_2_5_102_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP273120"},{"key":"e_1_2_5_103_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2016.02.014"},{"key":"e_1_2_5_104_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.116.004229"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP286845","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T18:16:46Z","timestamp":1748369806000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP286845"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,14]]},"references-count":103,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1113\/JP286845"],"URL":"https:\/\/doi.org\/10.1113\/jp286845","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,14]]},"assertion":[{"value":"2024-04-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}