Lem2 Is Essential for Cardiac Development by Maintaining Nuclear Integrity

This study investigates the role of the nuclear envelope protein Lem2 in protecting cardiomyocyte nuclei from mechanically induced damage during cardiac development. Using cardiomyocyte-specific Lem2 knockout mouse models, the authors demonstrate that Lem2 is essential during fetal heart development, where its absence leads to nuclear rupture, DNA damage, apoptosis, and embryonic lethality. Mechanistically, nuclear damage was shown to be driven by muscle contraction–derived mechanical forces rather than external matrix stiffness. In contrast, partial Lem2 depletion in adult cardiomyocytes did not impair cardiac function or nuclear integrity, suggesting developmental stage–dependent mechanical vulnerability. These findings provide mechanistic insight into nuclear mechanotransduction pathways underlying inherited cardiomyopathies.