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The FK506-binding protein FKBP12 has been implicated in regulating the ryanodine receptor in skeletal muscle, but its role in cardiac muscle remains unclear. To define the effect of FKBP12 in cardiac function, we generated conditional mouse models of FKBP12 deficiency. We used Cre recombinase driven by either the \u03b1-myosin heavy chain, (\u03b1MHC) or muscle creatine kinase (MCK) promoter, which are expressed at embryonic day 9 (E9) and E13, respectively. Both conditional models showed an almost total loss of FKBP12 in adult hearts compared with control animals. However, only the early embryonic deletion of FKBP12 (\u03b1MHC-Cre) resulted in an early-onset and progressive DCM, increased cardiac oxidative stress, altered expression of proteins associated with cardiac remodeling and disease, and sarcoplasmic reticulum Ca2+ leak. Our findings indicate that FKBP12 deficiency during early development results in cardiac remodeling and altered expression of DCM-associated proteins that lead to progressive DCM in adult hearts, thus suggesting a major role for FKBP12 in embryonic cardiac muscle.<\/jats:p>","DOI":"10.1085\/jgp.202413583","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T02:20:34Z","timestamp":1729650034000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Mechanisms underlying dilated cardiomyopathy associated with FKBP12 deficiency"],"prefix":"10.1085","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6418-6666","authenticated-orcid":true,"given":"Amy D.","family":"Hanna","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02pttbw34","id-type":"ROR","asserted-by":"publisher"}],"name":"Baylor College of Medicine 1 Department of Integrative Physiology, , Houston, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0634-6478","authenticated-orcid":true,"given":"Ting","family":"Chang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02pttbw34","id-type":"ROR","asserted-by":"publisher"}],"name":"Baylor College of Medicine 1 Department of Integrative Physiology, , Houston, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0015-5339","authenticated-orcid":true,"given":"Kevin S.","family":"Ho","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02pttbw34","id-type":"ROR","asserted-by":"publisher"}],"name":"Baylor College of Medicine 1 Department of Integrative Physiology, , Houston, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6737-1947","authenticated-orcid":true,"given":"Rachel Sue Zhen","family":"Yee","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02pttbw34","id-type":"ROR","asserted-by":"publisher"}],"name":"Baylor College of Medicine 1 Department of Integrative Physiology, , Houston, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3708-8560","authenticated-orcid":true,"given":"William Cameron","family":"Walker","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02pttbw34","id-type":"ROR","asserted-by":"publisher"}],"name":"Baylor College of Medicine 1 Department of Integrative Physiology, , Houston, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5011-766X","authenticated-orcid":true,"given":"Nadia","family":"Agha","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02pttbw34","id-type":"ROR","asserted-by":"publisher"}],"name":"Baylor College of Medicine 1 Department of Integrative Physiology, , Houston, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9591-9567","authenticated-orcid":true,"given":"Chih-Wei","family":"Hsu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02pttbw34","id-type":"ROR","asserted-by":"publisher"}],"name":"Baylor College of Medicine 1 Department of Integrative Physiology, , Houston, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1521-7977","authenticated-orcid":true,"given":"Sung Yun","family":"Jung","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02pttbw34","id-type":"ROR","asserted-by":"publisher"}],"name":"Baylor College of Medicine 2 Department of Biochemistry, , Houston, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4372-9638","authenticated-orcid":true,"given":"Mary E.","family":"Dickinson","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02pttbw34","id-type":"ROR","asserted-by":"publisher"}],"name":"Baylor College of Medicine 1 Department of Integrative Physiology, , Houston, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7472-1156","authenticated-orcid":true,"given":"Md. 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