{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T23:16:18Z","timestamp":1768518978483,"version":"3.49.0"},"posted":{"date-parts":[[2024,10,27]]},"group-title":"Genetics","reference-count":28,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,10,27]],"date-time":"2024-10-27T00:00:00Z","timestamp":1729987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,10,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Dysregulated proteostasis in cardiomyocytes is an important pathological event in\n                  <jats:italic>BAG3<\/jats:italic>\n                  cardiomyopathy, which can be repaired by inhibiting mechanistic target of rapamycin (mTOR) for cardioprotective effects. Here, we aimed to uncover additional pathological events and therapeutic target genes via leveraging zebrafish genetics. We first assessed transcription factor EB (\n                  <jats:italic>tfeb<\/jats:italic>\n                  ), a candidate gene that encodes a direct downstream phosphorylation target of mTOR signaling. We found that cardiomyocyte-specific transgenic overexpression of\n                  <jats:italic>tfeb<\/jats:italic>\n                  (\n                  <jats:italic>Tg[cmlc2:tfeb]<\/jats:italic>\n                  ) is sufficient to repair defective proteostasis, attenuate accelerated cardiac senescence, a previously unrecognized phenotype in the\n                  <jats:italic>bag3<\/jats:italic>\n                  cardiomyopathy model, and rescue cardiac dysfunction. Next, we compared cardiac transcriptomes between the\n                  <jats:italic>Tg(cmlc2:tfeb)<\/jats:italic>\n                  transgenic fish and the\n                  <jats:italic>\n                    mtor\n                    <jats:sup>xu015\/+<\/jats:sup>\n                  <\/jats:italic>\n                  mutant, and tested 4 commonly downregulated lipodystrophy genes using an F0-based genetic assay. We found that inhibition of the fatty acid binding protein a (\n                  <jats:italic>fabp7a<\/jats:italic>\n                  ) gene, but not the other 3 genes, exerts therapeutic effects on\n                  <jats:italic>bag3<\/jats:italic>\n                  cardiomyopathy. Conversely,\n                  <jats:italic>fabp7a<\/jats:italic>\n                  expression is elevated in\n                  <jats:italic>bag3<\/jats:italic>\n                  cardiomyopathy model and cardiomyocyte-specific overexpression of\n                  <jats:italic>fabp7a<\/jats:italic>\n                  resulted in dysregulated proteostasis, accelerated cardiac senescence, as well as cardiac dysfunction. Together, these genetic studies in zebrafish uncovered Fabp7a activation and accelerated cardiac senescence as important pathological events in\n                  <jats:italic>bag3<\/jats:italic>\n                  cardiomyopathy. The mTOR-Tfeb-Fabp7a signaling axis can be harnessed to repair these pathological changes and exert cardioprotective effects.\n                <\/jats:p>","DOI":"10.1101\/2024.10.24.620101","type":"posted-content","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:50:12Z","timestamp":1730076612000},"source":"Crossref","is-referenced-by-count":0,"title":["An mTOR-Tfeb-Fabp7a signaling axis can be harnessed to ameliorate\n                  <i>bag3<\/i>\n                  cardiomyopathy in adult zebrafish"],"prefix":"10.64898","author":[{"given":"Yonghe","family":"Ding","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feixiang","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baul","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David Mondaca","family":"Ruff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueying","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaolei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024103009300727000_2024.10.24.620101v1.1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.305372"},{"key":"2024103009300727000_2024.10.24.620101v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.01.016"},{"key":"2024103009300727000_2024.10.24.620101v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehr105"},{"key":"2024103009300727000_2024.10.24.620101v1.4","doi-asserted-by":"publisher","DOI":"10.1172\/JCI95839"},{"key":"2024103009300727000_2024.10.24.620101v1.5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1803130115"},{"key":"2024103009300727000_2024.10.24.620101v1.6","doi-asserted-by":"crossref","unstructured":"Ding Y , Dvornikov AV , Ma X , Zhang H , Wang Y , Lowerison M , Packard RR , Wang L , Chen J , Zhang Y , Hsiai T , Lin X and Xu X . Haploinsufficiency of mechanistic target of rapamycin ameliorates bag3 cardiomyopathy in adult zebrafish. Dis Model Mech. 2019;12.","DOI":"10.1242\/dmm.040154"},{"key":"2024103009300727000_2024.10.24.620101v1.7","doi-asserted-by":"publisher","DOI":"10.4161\/auto.19653"},{"key":"2024103009300727000_2024.10.24.620101v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-022-01028-6"},{"key":"2024103009300727000_2024.10.24.620101v1.9","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202357574"},{"key":"2024103009300727000_2024.10.24.620101v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2017.10.003"},{"key":"2024103009300727000_2024.10.24.620101v1.11","doi-asserted-by":"crossref","unstructured":"Linders AN , Dias IB , Lopez Fernandez T , Tocchetti CG , Bomer N and Van der Meer P . A review of the pathophysiological mechanisms of doxorubicin-induced cardiotoxicity and aging. NPJ Aging. 2024;10:9.","DOI":"10.1038\/s41514-024-00135-7"},{"key":"2024103009300727000_2024.10.24.620101v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2022.11.001"},{"key":"2024103009300727000_2024.10.24.620101v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2009.29"},{"key":"2024103009300727000_2024.10.24.620101v1.14","doi-asserted-by":"publisher","DOI":"10.1186\/1479-7364-5-3-170"},{"key":"2024103009300727000_2024.10.24.620101v1.15","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr306"},{"key":"2024103009300727000_2024.10.24.620101v1.16","doi-asserted-by":"crossref","unstructured":"Rezar R , Jirak P , Gschwandtner M , Derler R , Felder TK , Haslinger M , Kopp K , Seelmaier C , Granitz C , Hoppe UC and Lichtenauer M . Heart-Type Fatty Acid-Binding Protein (H-FABP) and its Role as a Biomarker in Heart Failure: What Do We Know So Far? J Clin Med. 2020;9.","DOI":"10.3390\/jcm9010164"},{"key":"2024103009300727000_2024.10.24.620101v1.17","doi-asserted-by":"crossref","unstructured":"George Warren W , Osborn M , Yates A and O\u2019Sullivan SE . The emerging role of fatty acid binding protein 7 (FABP7) in cancers. Drug Discov Today. 2024;29:103980.","DOI":"10.1016\/j.drudis.2024.103980"},{"key":"2024103009300727000_2024.10.24.620101v1.18","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1602663"},{"key":"2024103009300727000_2024.10.24.620101v1.19","doi-asserted-by":"crossref","unstructured":"Kim M , Lu L , Dvornikov AV , Ma X , Ding Y , Zhu P , Olson TM , Lin X and Xu X. TFEB Overexpression, Not mTOR Inhibition, Ameliorates RagC(S75Y) Cardiomyopathy. Int J Mol Sci. 2021;22.","DOI":"10.3390\/ijms22115494"},{"key":"2024103009300727000_2024.10.24.620101v1.20","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13835"},{"key":"2024103009300727000_2024.10.24.620101v1.21","doi-asserted-by":"crossref","unstructured":"Ding Y , Wang M , Bu H , Li J , Lin X and Xu X . Application of an F0-based genetic assay in adult zebrafish to identify modifier genes of an inherited cardiomyopathy. Dis Model Mech. 2023;16.","DOI":"10.1242\/dmm.049427"},{"key":"2024103009300727000_2024.10.24.620101v1.22","doi-asserted-by":"publisher","DOI":"10.1172\/JCI94310"},{"key":"2024103009300727000_2024.10.24.620101v1.23","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.26482"},{"key":"2024103009300727000_2024.10.24.620101v1.24","doi-asserted-by":"crossref","unstructured":"Lu H , Sun J , Hamblin MH , Chen YE and Fan Y . Transcription factor EB regulates cardiovascular homeostasis. EBioMedicine. 2021;63:103207.","DOI":"10.1016\/j.ebiom.2020.103207"},{"key":"2024103009300727000_2024.10.24.620101v1.25","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.248260"},{"key":"2024103009300727000_2024.10.24.620101v1.26","doi-asserted-by":"crossref","unstructured":"Zhang H , Dvornikov AV , Huttner IG , Ma X , Santiago CF , Fatkin D and Xu X . A Langendorff-like system to quantify cardiac pump function in adult zebrafish. Dis Model Mech. 2018;11.","DOI":"10.1242\/dmm.034819"},{"key":"2024103009300727000_2024.10.24.620101v1.27","doi-asserted-by":"crossref","unstructured":"Brinkman EK and van Steensel B . Rapid Quantitative Evaluation of CRISPR Genome Editing by TIDE and TIDER. Methods Mol Biol. 2019;1961:29\u201344.","DOI":"10.1007\/978-1-4939-9170-9_3"},{"key":"2024103009300727000_2024.10.24.620101v1.28","first-page":"e166","article-title":"atg7- Based Autophagy Activation Reverses Doxorubicin-Induced Cardiotoxicity","volume":"129","year":"2021","journal-title":"Circ Res"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.10.24.620101","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T07:20:38Z","timestamp":1768461638000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.10.24.620101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,27]]},"references-count":28,"URL":"https:\/\/doi.org\/10.1101\/2024.10.24.620101","relation":{},"subject":[],"published":{"date-parts":[[2024,10,27]]},"subtype":"preprint"}}