{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T14:47:09Z","timestamp":1788446829052,"version":"build-2803163510"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"18","license":[{"start":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T00:00:00Z","timestamp":1697414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017268","name":"Berlin Institute of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100017268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010447","name":"German Centre for Cardiovascular Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010447","name":"Deutsches Zentrum f\u00fcr Herz-Kreislauf-Forschung","doi-asserted-by":"publisher","award":["81Z0100216"],"award-info":[{"award-number":["81Z0100216"]}],"id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["422215721"],"award-info":[{"award-number":["422215721"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,2,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Mutation of the PRDM16 gene causes human dilated and non-compaction cardiomyopathy. The PRDM16 protein is a transcriptional regulator that affects cardiac development via Tbx5 and Hand1, thus regulating myocardial structure. The biallelic inactivation of Prdm16 induces severe cardiac dysfunction with post-natal lethality and hypertrophy in mice. The early pathological events that occur upon Prdm16 inactivation have not been explored.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>This study performed in-depth pathophysiological and molecular analyses of male and female Prdm16csp1\/wt mice that carry systemic, monoallelic Prdm16 gene inactivation. We systematically assessed early molecular changes through transcriptomics, proteomics, and metabolomics. Kinetic modelling of cardiac metabolism was performed in silico with CARDIOKIN. Prdm16csp1\/wt mice are viable up to 8 months, develop hypoplastic hearts, and diminished systolic performance that is more pronounced in female mice. Prdm16csp1\/wt cardiac tissue of both sexes showed reductions in metabolites associated with amino acid as well as glycerol metabolism, glycolysis, and the tricarboxylic acid cycle. Prdm16csp1\/wt cardiac tissue revealed diminished glutathione (GSH) and increased inosine monophosphate (IMP) levels indicating oxidative stress and a dysregulated energetics, respectively. An accumulation of triacylglycerides exclusively in male Prdm16csp1\/wt hearts suggests a sex-specific metabolic adaptation. Metabolic modelling using CARDIOKIN identified a reduction in fatty acid utilization in males as well as lower glucose utilization in female Prdm16csp1\/wt cardiac tissue. On the level of transcripts and protein expression, Prdm16csp1\/wt hearts demonstrate an up-regulation of pyridine nucleotide-disulphide oxidoreductase domain 2 (Pyroxd2) and the transcriptional regulator pre-B-cell leukaemia transcription factor interacting protein 1 (Pbxip1). The strongest concordant transcriptional up-regulation was detected for Prdm16 itself, probably through an autoregulatory mechanism.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Monoallelic, global Prdm16 mutation diminishes cardiac performance in Prdm16csp1\/wt mice. Metabolic alterations and transcriptional dysregulation in Prdm16csp1\/wt affect cardiac tissue. Female Prdm16csp1\/wt mice develop a more pronounced phenotype, indicating sexual dimorphism at this early pathological window. This study suggests that metabolic dysregulation is an early event in the PRDM16 associated cardiac pathology.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvad154","type":"journal-article","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T10:45:01Z","timestamp":1697453101000},"page":"2902-2916","source":"Crossref","is-referenced-by-count":17,"title":["<i>Prdm16<\/i> mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators"],"prefix":"10.1093","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4744-5421","authenticated-orcid":false,"given":"Jirko","family":"K\u00fchnisch","sequence":"first","affiliation":[{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Berlin , Germany"},{"name":"Experimental and Clinical Research Center, Lindenberger Weg 80, 13125 Berlin , Germany"},{"name":"Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC) , Berlin , Germany"},{"name":"DZHK (German Centre for Cardiovascular Research), partner site Berlin , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Theisen","sequence":"additional","affiliation":[{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Berlin , Germany"},{"name":"Experimental and Clinical Research Center, Lindenberger Weg 80, 13125 Berlin , Germany"},{"name":"Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC) , Berlin , Germany"},{"name":"DZHK (German Centre for Cardiovascular Research), partner site Berlin , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7947-2881","authenticated-orcid":false,"given":"Josephine","family":"Dartsch","sequence":"additional","affiliation":[{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , Berlin , Germany"},{"name":"Experimental and Clinical Research Center, Lindenberger Weg 80, 13125 Berlin , Germany"},{"name":"Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC) , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6965-0226","authenticated-orcid":false,"given":"Raphaela","family":"Fritsche-Guenther","sequence":"additional","affiliation":[{"name":"BIH Metabolomics Platform, Berlin Institute of Health (BIH) at Charit\u00e9 - Universit\u00e4tsmedizin Berlin , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7049-534X","authenticated-orcid":false,"given":"Marieluise","family":"Kirchner","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Center for Molecular Medicine in the Helmholtz Association (MDC), Proteomics Platform , Berlin , Germany"},{"name":"Berlin Institute of Health (BIH) at Charit\u00e9 - Universit\u00e4tsmedizin Berlin , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9116-630X","authenticated-orcid":false,"given":"Benedikt","family":"Obermayer","sequence":"additional","affiliation":[{"name":"Core Unit Bioinformatics, Berlin Institute of Health at Charit\u00e9 - Universit\u00e4tsmedizin Berlin , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Bauer","sequence":"additional","affiliation":[{"name":"BIH Metabolomics Platform, Berlin Institute of 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2245-528X","authenticated-orcid":false,"given":"Philipp","family":"Mertins","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Center for Molecular Medicine in the Helmholtz Association (MDC), Proteomics Platform , Berlin , Germany"},{"name":"Berlin Institute of Health (BIH) at Charit\u00e9 - Universit\u00e4tsmedizin Berlin , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5423-1651","authenticated-orcid":false,"given":"Jennifer A","family":"Kirwan","sequence":"additional","affiliation":[{"name":"BIH Metabolomics Platform, Berlin Institute of Health (BIH) at Charit\u00e9 - Universit\u00e4tsmedizin Berlin , Berlin , 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