{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:17:00Z","timestamp":1768508220202,"version":"3.49.0"},"posted":{"date-parts":[[2023,10,2]]},"group-title":"Cell Biology","reference-count":51,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,10,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Obesity and type 2 diabetes are at epidemic levels and a significant proportion of these patients are diagnosed with left ventricular hypertrophy.\n                  <jats:bold>\n                    <jats:italic>CREB<\/jats:italic>\n                    R\n                  <\/jats:bold>\n                  egulated\n                  <jats:bold>T<\/jats:bold>\n                  ranscription\n                  <jats:bold>C<\/jats:bold>\n                  o-activator (\n                  <jats:bold>\n                    <jats:italic>CRTC<\/jats:italic>\n                  <\/jats:bold>\n                  ) is a key regulator of metabolism in mammalian hepatocytes, where it is activated by calcineurin (CaN) to increase expression of gluconeogenic genes. CaN is known its role in pathological cardiac hypertrophy, however, a role for CRTC in the heart has not been identified. In\n                  <jats:italic>Drosophila<\/jats:italic>\n                  ,\n                  <jats:italic>CRTC<\/jats:italic>\n                  null mutants have little body fat and exhibit severe cardiac restriction, myofibrillar disorganization, cardiac fibrosis and tachycardia, all hallmarks of heart disease. Cardiac-specific knockdown of\n                  <jats:italic>CRTC<\/jats:italic>\n                  , or its coactivator\n                  <jats:italic>CREBb<\/jats:italic>\n                  , mimicked the reduced body fat and heart defects of\n                  <jats:italic>CRTC<\/jats:italic>\n                  null mutants. Comparative gene expression in\n                  <jats:italic>CRTC<\/jats:italic>\n                  loss- or gain-of-function fly hearts revealed contra-regulation of genes involved in glucose, fatty acid, and amino acid metabolism, suggesting that\n                  <jats:italic>CRTC<\/jats:italic>\n                  also acts as a metabolic switch in the heart. Among the contra-regulated genes with conserved CREB binding sites, we identified the fly ortholog of\n                  <jats:italic>Sarcalumenin,<\/jats:italic>\n                  which is a Ca\n                  <jats:sup>2+<\/jats:sup>\n                  -binding protein in the sarcoplasmic reticulum. Cardiac knockdown recapitulated the loss of CRTC cardiac restriction and fibrotic phenotypes, suggesting it is a downstream effector of\n                  <jats:italic>CRTC<\/jats:italic>\n                  we named\n                  <jats:italic>thinman<\/jats:italic>\n                  (\n                  <jats:italic>tmn<\/jats:italic>\n                  ). Importantly, cardiac overexpression of either CaN or\n                  <jats:italic>CRTC<\/jats:italic>\n                  in flies caused hypertrophy that was reversed in a\n                  <jats:italic>CRTC<\/jats:italic>\n                  mutant background, suggesting CRTC mediates hypertrophy downstream of CaN, perhaps as an alternative to NFAT. CRTC novel role in the heart is likely conserved in vertebrates as knockdown in zebrafish also caused cardiac restriction, as in fl ies. These data suggest that CRTC is involved in myocardial cell maintenance and that CaN-CRTC- Sarcalumenin\/\n                  <jats:italic>tmn<\/jats:italic>\n                  signaling represents a novel and conserved pathway underlying cardiac hypertrophy.\n                <\/jats:p>","DOI":"10.1101\/2023.10.02.560407","type":"posted-content","created":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T22:55:21Z","timestamp":1696287321000},"source":"Crossref","is-referenced-by-count":0,"title":["The nutrient sensor CRTC &amp; Sarcalumenin \/ Thinman represent a new pathway in cardiac hypertrophy"],"prefix":"10.64898","author":[{"given":"Cristiana","family":"Dondi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8303-3531","authenticated-orcid":false,"given":"Georg","family":"Vogler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anjali","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanley M.","family":"Walls","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana\u00efs","family":"Kervadec","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michaela R.","family":"Romero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soda B.","family":"Diop","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Goode","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John B.","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandre 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