Metabolic reprograming-driven programmed embryonic cardiomyocyte senescence shapes cardiac chambers

Metabolic reprograming-driven programmed embryonic cardiomyocyte senescence shapes cardiac chambers | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Metabolic reprograming-driven programmed embryonic cardiomyocyte senescence shapes cardiac chambers Michel PUCEAT, Audrey IBRE, Stéphanie IBRAHIM, Bernd Jagla, Alexandra MARTIN This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8756669/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract The growing and yet beating embryonic heart requires nutriments and oxygenation. In the absence of the coronary system to feed the organ up to mid-gestation, formation of the heart relies on transient trabeculae that extend from the myocardial wall into the chamber and increase exchange surface. How trabeculae are formed has been recently uncovered. How they coalesce during ventricular wall thickening and compaction is a long-lasting and still unresolved question, while their persistence after birth provides the young patient with a high risk of heart failure at adulthood. Here, we combine single cell-omics, pharmacological and genetic invalidations of proteins in mice, High Resolution Episcopic Microscopy and 3D heart imaging to report that a TGF- and a metabolism-driven program of embryonic senescence occurs at mid-gestation in both mouse and human trabeculae cardiomyocytes. The senescent myocytes with a unique transcriptomic signature induce reprograming of neighbor myocytes. Dedifferentiated myocytes undergo YAP-mediated EMT, proliferate and contribute to the thickening of the ventricular wall. Macrophages terminate the whole process by scavenging senescent myocytes further leading to a regression of trabeculae and initiation of ventricular compaction. Deletion of cdkn1a(p21), inhibition of TGF signaling, perturbation of metabolism or deletion of embryonic macrophages leads to hyper-trabeculation, and defects in compaction. Exacerbation of cardiomyocyte senescence by a cyclin-dependent kinases 4/6 inhibitor unbalances the biological process and leads to non-compaction and dilated cardiomyopathy. We show that a myocardial specific and finely-tuned program of embryonic cell senescence, conserved during evolution initiates cardiac compaction allowing for a proper patterning of cardiac chambers Biological sciences/Developmental biology/Senescence Biological sciences/Cell biology/Senescence Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Video1WTP21redGBL1greenE16.avi video 1 supplementaryfiguresIbreetal.pdf supplementary figures Video2WtP21redPHH3greenE16.avi video 2 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8756669","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":586450148,"identity":"0be82427-85a0-49b1-a1e0-7331e6437916","order_by":0,"name":"Michel 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