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Edited by Janet Rossant, The Gairdner Foundation, Toronto, ON, Canada, and approved November 24, 2020 (received for review May 6, 2020)
Significance
Mature cardiomyocytes are highly adapted to pump efficiently over billions of cycles. The mechanisms that regulate and coordinate the acquisition of the specialized features of mature cardiomyocytes in the postnatal period are not well understood. This knowledge gap hinders studies of disease pathogenesis and the maturation of stem cell–derived cardiomyocytes for cardiac regenerative medicine. Here, we studied the roles of sarcomeres, the contractile machinery of cardiomyocytes, in regulating cardiomyocyte maturation. Using an in vivo genetic mosaic approach to circumvent animal lethality and secondary consequences of cardiac dysfunction, we analyzed the contribution of sarcomeres to cardiomyocyte maturation in a physiological context. We identified an important role of sarcomeres in the regulation of signal transduction and gene transcription.
Abstract
The paucity of knowledge about cardiomyocyte maturation is a major bottleneck in cardiac regenerative medicine. In development, cardiomyocyte maturation is characterized by orchestrated structural, transcriptional, and functional specializations that occur mainly at the perinatal stage. Sarcomeres are the key cytoskeletal structures that regulate the ultrastructural maturation of other organelles, but whether sarcomeres modulate the signal transduction pathways that are essential for cardiomyocyte maturation remains unclear. To address this question, here we generated mice with cardiomyocyte-specific, mosaic, and hypomorphic mutations of α-actinin-2 (Actn2) to study the cell-autonomous roles of sarcomeres in postnatal cardiomyocyte maturation. Actn2 mutation resulted in defective structural maturation of transverse-tubules and mitochondria. In addition, Actn2 mutation triggered transcriptional dysregulation, including abnormal expression of key sarcomeric and mitochondrial genes, and profound impairment of the normal progression of maturational gene expression. Mechanistically, the transcriptional changes in Actn2 mutant cardiomyocytes strongly correlated with those in cardiomyocytes deleted of serum response factor (SRF), a critical transcription factor that regulates cardiomyocyte maturation. Actn2 mutation increased the monomeric form of cardiac α-actin, which interacted with the SRF cofactor MRTFA and perturbed its nuclear localization. Overexpression of a dominant-negative MRTFA mutant was sufficient to recapitulate the morphological and transcriptional defects in Actn2 and Srf mutant cardiomyocytes. Together, these data indicate that Actn2-based sarcomere organization regulates structural and transcriptional maturation of cardiomyocytes through MRTF-SRF signaling.
Footnotes
↵1Y.G., Y.C., and B.D.J. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: guo{at}bjmu.edu.cn or William.Pu{at}cardio.chboston.org.
↵3Present address: School of Basic Medical Sciences, Institute of Cardiovascular Sciences, Peking University Health Science Center; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, 100191, China.
Author contributions: Y.G., Y.C., and W.T.P. designed research; Y.G., Y.C., B.D.J., Q.M., B.M., E.C.T., and N.M. performed research; Y.G., B.M., E.C.T., M.A.T., E.M.S., and A.H.B. contributed new reagents/analytic tools; Y.G., Y.C., B.D.J., I.S., G.-C.Y., and W.T.P. analyzed data; Y.G. and W.T.P. wrote the paper; and M.A.T. and E.M.S. provided MRTF mice.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2008861118/-/DCSupplemental.
Data Availability.
RNA-Seq data generated for this study have been deposited in the Gene Expression Omnibus database under the accession code GSE136096. Actn2F mice, produced in Dr. Alan Beggs’s laboratory, can be obtained through a material transfer agreement.
Published under the PNAS license.
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Sarcomeres regulate murine cardiomyocyte maturation through MRTF-SRF signaling
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