Sarcomeres regulate cardiomyocyte maturation through MRTF SRF signaling

Cardiomyocyte maturation is essential for robust heart contraction throughout life. The signaling networks governing cardiomyocyte maturation remain poorly defined. Our prior studies established the transcription factor SRF as a key regulator of the assembly of sarcomeres, the contractile unit of cardiomyocytes. Whether sarcomeres regulate other aspects of maturation remains unclear. Here we generated mice with cardiomyocyte specific, mosaic mutation of α-actinin-2 (Actn2), a key organizer of sarcomeres, to study its cell-autonomous role in cardiomyocyte maturation. In addition to the expected structural defects, Actn2 mutation triggered dramatic transcriptional dysregulation, which strongly correlated with transcriptional changes observed in SRF depleted cardiomyocytes. Actn2 mutation increased monomeric actin, which perturbed the nuclear localization of the SRF cofactor MRTFA. Overexpression of a dominantnegative MRTFA mutant was sufficient to recapitulate the transcriptional and morphological defects in Actn2 and Srf mutant cardiomyocytes. Together, we demonstrate that ACTN2-based sarcomere assembly and MRTF-SRF signaling establish a positive feedback loop that promotes cardiomyocyte maturation.