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Here we compared the effect of phosphomimetic (D282) and wild-type (S282) cMyBP-C gene transfer on the HCM phenotype of engineered heart tissues (EHTs) generated from a mouse model carrying a <jats:italic>Mybpc3<\/jats:italic> mutation (KI). KI EHTs showed lower levels of mutant <jats:italic>Mybpc3<\/jats:italic> mRNA and protein, and altered gene expression compared with\u00a0wild-type (WT) EHTs. Furthermore, KI EHTs exhibited faster spontaneous contractions and higher maximal force and sensitivity to external [Ca<jats:sup>2+<\/jats:sup>] under pacing. Adeno-associated virus-mediated gene transfer of D282 and S282 similarly restored <jats:italic>Mybpc3<\/jats:italic> mRNA and protein levels and suppressed mutant <jats:italic>Mybpc3<\/jats:italic> transcripts. Moreover, both exogenous cMyBP-C proteins were properly incorporated in the sarcomere. KI EHTs hypercontractility was similarly prevented by both treatments, but S282 had a stronger effect than D282 to normalize the force-Ca<jats:sup>2+<\/jats:sup>-relationship and the expression of dysregulated genes. These findings in an <jats:italic>in vitro<\/jats:italic> model indicate that S282 is a better choice than D282 to restore the HCM EHT phenotype. To which extent the results apply to human HCM remains to be seen.<\/jats:p>","DOI":"10.1038\/s41598-019-54665-2","type":"journal-article","created":{"date-parts":[[2019,12,3]],"date-time":"2019-12-03T11:04:18Z","timestamp":1575371058000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Phosphomimetic cardiac myosin-binding protein C partially rescues a cardiomyopathy phenotype in murine engineered heart tissue"],"prefix":"10.1038","volume":"9","author":[{"given":"Alexander","family":"Dutsch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J. 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