{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T15:20:01Z","timestamp":1773933601893,"version":"3.50.1"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01HL130072"],"award-info":[{"award-number":["R01HL130072"]}]},{"name":"NIH","award":["R01HL155993"],"award-info":[{"award-number":["R01HL155993"]}]},{"name":"NIH","award":["R01HL160665"],"award-info":[{"award-number":["R01HL160665"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>RBFOX1 is an RNA-binding protein that regulates alternative splicing and RNA processing in the neurons, skeletal muscle, and heart. We intended to define the role of RBFOX1 in regulating calcium homeostasis to maintain normal cardiac function. We generated cardiomyocyte-specific Rbfox1 gene-deletion mice (cKO). The cardiomyocyte-specific deletion of RBFOX1 was confirmed by Western blotting and immunohistochemistry. The cKO mice showed mild hypertrophy and depressed cardiac function under homeostatic conditions, which did not deteriorate with age. Pressure overload by trans-aortic constriction (TAC) caused exaggerated cardiac hypertrophy and accelerated heart failure in cKO compared with wild-type mice. We performed Western blotting to assess the expression of important Ca2+-handling proteins, which showed alterations in the phosphorylation of PLN and CAMKII and decreased expression of SERCA2. We measured the Ca2+ dynamics and noted significantly delayed Ca2+ reuptake into the sarcoplasmic reticulum. Importantly, the decrease in SERCA2 expression was not due to reduced mRNA expression or altered splicing. To assess the possibility of the post-transcriptional regulation of SERCA2 expression by RBFOX1, we performed RNA immunoprecipitation (RIP), which showed the binding of RBFOX1 protein to Serca2 mRNA, which was confirmed in luciferase assays with the Serca2a 3\u2032-untranslated region fused to luciferase. Finally, we performed a puromycin incorporation experiment, which showed that RBFOX1 enhances SERCA2 protein translation. Our results show that RBFOX1 plays a crucial role in regulating the expression of Ca2+-handling genes to maintain normal cardiac function. We show an important post-transcriptional role of RBFOX1 in regulating SERCA2 expression.<\/jats:p>","DOI":"10.3390\/cells14090664","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:35:13Z","timestamp":1746185713000},"page":"664","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["RBFOX1 Regulates Calcium Signaling and Enhances SERCA2 Translation"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4733-5751","authenticated-orcid":false,"given":"Sadiq","family":"Umar","sequence":"first","affiliation":[{"name":"Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA"},{"name":"Department of Oral Biology, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5217-7789","authenticated-orcid":false,"given":"Wuqiang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA"},{"name":"Department of Cardiovascular Medicine, Physiology and Biomedical Engineering, Mayo Clinic Arizona, Phoenix, AZ 85059, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Souza-Neto","sequence":"additional","affiliation":[{"name":"Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingrid","family":"Bender","sequence":"additional","affiliation":[{"name":"Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0864-0208","authenticated-orcid":false,"given":"Steven C.","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chastity L.","family":"Healy","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy D.","family":"O\u2019Connell","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9229-4429","authenticated-orcid":false,"given":"Jop H.","family":"van Berlo","sequence":"additional","affiliation":[{"name":"Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA"},{"name":"Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1172\/JCI62839","article-title":"Signaling effectors underlying pathologic growth and remodeling of the heart","volume":"123","author":"Maillet","year":"2013","journal-title":"J. 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