Sarcomeres regulate murine cardiomyocyte maturation through MRTF-SRF signaling

Area of Science:

• Cardiovascular Biology
• Cellular and Molecular Medicine
• Regenerative Medicine

Background:

• Cardiomyocyte maturation is essential for cardiac function but poorly understood, hindering cardiac regenerative medicine.
• Sarcomeres, the main cytoskeletal structures, are implicated in cardiomyocyte maturation, yet their role in signaling pathways remains unclear.

Purpose of the Study:

• To investigate the cell-autonomous roles of sarcomeres in postnatal cardiomyocyte maturation.
• To elucidate the molecular mechanisms by which sarcomeres influence cardiomyocyte structural and transcriptional development.

Main Methods:

• Generation of mice with cardiomyocyte-specific, mosaic, hypomorphic mutations in alpha-actinin-2 (Actn2).
• Analysis of structural (transverse-tubules, mitochondria) and transcriptional changes in mutant cardiomyocytes.
• Investigation of the interaction between Actn2, alpha-actin, MRTFA, and serum response factor (SRF).

Main Results:

• Actn2 mutations led to defective structural maturation of transverse-tubules and mitochondria.
• Transcriptional dysregulation was observed, including abnormal expression of sarcomeric and mitochondrial genes.
• Actn2 mutation perturbed MRTF-SRF signaling by increasing monomeric alpha-actin, affecting MRTFA nuclear localization.

Conclusions:

• Sarcomere organization, through Actn2, is critical for both structural and transcriptional maturation of cardiomyocytes.
• The MRTF-SRF signaling pathway is a key mediator of Actn2-dependent cardiomyocyte maturation.
• Findings provide insights into cardiomyocyte development and potential targets for cardiac regeneration.