{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T09:13:44Z","timestamp":1774602824208,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,24]]},"group-title":"Physiology","reference-count":28,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["19CDA34680003"],"award-info":[{"award-number":["19CDA34680003"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R01HL158703"],"award-info":[{"award-number":["R01HL158703"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["R01DK122205"],"award-info":[{"award-number":["R01DK122205"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Pathologic cardiac hypertrophy requires increased protein synthesis, but the mechanosensors that link membrane stretch to translational control remain poorly understood. Polycystin-1 (PC1), encoded by\n                  <jats:italic>PKD1<\/jats:italic>\n                  , has been proposed as a cardiac mechanosensor, with its C-terminal tail (PC1-CT) promoting hypertrophy in rodent cardiomyocytes. However, its subcellular localization and downstream signaling remain incompletely defined, especially in human cardiomyocytes.\n                <\/jats:p>\n                <jats:p>Here, we examined endogenous PC1 C-terminus localization and the effects of adenoviral PC1-CT overexpression in human iPSC-derived ventricular cardiomyocytes (hiPSC-CMs) and adult mouse ventricular myocytes. Immunofluorescence revealed a striking striated pattern for both endogenous PC1 C-terminus (detected with a PC1-CT antibody) and the overexpressed PC1-CT fragment. In hiPSC-CMs, the PC1 C-terminus localized between the \u03b1-actinin bands. In contrast, in adult cardiomyocytes, the overexpressed protein colocalized with \u03b1-actinin and desmin, suggesting that PC1-CT sarcomeric distribution depends on cardiomyocyte maturation.<\/jats:p>\n                <jats:p>\n                  We performed RNA-seq to assess transcriptional responses downstream of PC1-CT overexpression in hiPSC-CMs relative to LacZ controls. Gene Set Enrichment Analysis (GSEA) revealed enrichment of gene sets related to ribosome biogenesis, RNA processing, and protein synthesis, while classical hypertrophic markers remained unchanged. Pathway analysis suggested increased PI3K activity. PC1-CT overexpression increased phosphorylation of Akt, ERK, S6K1, and ribosomal protein S6 without altering 4EBP1 phosphorylation, suggesting preferential activation of the mTOR-S6K1-S6 branch. Pharmacological studies showed that pan-PI3K inhibition abolished S6 phosphorylation, whereas MEK blockade did not affect it; pertussis toxin and PI3K\u03b3-selective inhibitors also did not affect S6, suggesting a G\n                  <jats:sub>i\/o<\/jats:sub>\n                  -independent PI3K\/Akt signaling driving mTOR-S6K1-S6 activation.\n                <\/jats:p>\n                <jats:p>Collectively, these data identify a sarcomere-associated pool of PC1-CT that engages PI3K-Akt-mTOR-S6K1-S6 signaling to enhance transcriptional programs related to ribosome biogenesis and protein synthesis, without activating a canonical hypertrophic gene program. These findings reveal a mechanistic link between PC1-CT and cardiomyocyte growth.<\/jats:p>","DOI":"10.64898\/2026.03.21.713243","type":"posted-content","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T22:20:13Z","timestamp":1774390813000},"source":"Crossref","is-referenced-by-count":0,"title":["Polycystin-1 C-Terminus Regulates Protein Synthesis-Related Pathways in Cardiomyocytes"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0628-000X","authenticated-orcid":false,"given":"Matthew","family":"Fiedler","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA"},{"name":"Program in Physiology, Biophysics & Systems Biology, Weill Cornell Medicine, NY, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2504-6270","authenticated-orcid":false,"given":"Alejandra","family":"Vasquez Limeta","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6906-8922","authenticated-orcid":false,"given":"Ernesto","family":"Reyes-Sanchez","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monserrat","family":"Reyes-Lozano","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0344-4160","authenticated-orcid":false,"given":"William","family":"Perez","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5869-6132","authenticated-orcid":false,"given":"Leah","family":"Carter","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2507-9398","authenticated-orcid":false,"given":"Christopher J.","family":"Ward","sequence":"additional","affiliation":[{"name":"The Jared Grantham Kidney Institute at the University of Kansas Medical Center, Department of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, KS, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1612-2729","authenticated-orcid":false,"given":"Francisco","family":"Altamirano","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA"},{"name":"Program in Physiology, Biophysics & Systems Biology, Weill Cornell Medicine, NY, NY, USA"},{"name":"Department of Cardiothoracic Surgery, Weill Cornell Medicine, NY, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026032701401385000_2026.03.21.713243v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra072139"},{"issue":"3","key":"2026032701401385000_2026.03.21.713243v1.2","doi-asserted-by":"crossref","first-page":"H622","DOI":"10.1152\/ajpheart.00277.2024","article-title":"The role of 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