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Phosphorylation of cardiac myosin-binding protein C (cMyBP-C), encoded by  MYBPC3 , increases the availability of myosin heads for interaction with actin thus enhancing contraction. cMyBP-C phosphorylation level is lower in septal myectomies of patients with hypertrophic cardiomyopathy (HCM) than in non-failing hearts. 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  Mybpc3  mutation (KI). KI EHTs showed lower levels of mutant  Mybpc3  mRNA and protein, and altered gene expression compared with wild-type (WT) EHTs. Furthermore, KI EHTs exhibited faster spontaneous contractions and higher maximal force and sensitivity to external [Ca 2+ ] under pacing. Adeno-associated virus-mediated gene transfer of D282 and S282 similarly restored  Mybpc3  mRNA and protein levels and suppressed mutant  Mybpc3  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 2+ -relationship and the expression of dysregulated genes. These findings in an  in vitro  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.

Phosphomimetic cardiac myosin-binding protein C partially rescues a cardiomyopathy phenotype in murine engineered heart tissue