Abstract Body: Background:
Hutchinson–Gilford progeria syndrome (HGPS), caused by a recurrent LMNA mutation leading to progerin accumulation, is characterized by premature aging and early mortality due to cardiovascular complications. While vascular pathology has been well studied, cardiomyocyte-intrinsic mechanisms remain poorly defined. Impaired gap junction communication has been reported in HGPS models; however, whether progerin directly disrupts cardiomyocyte coupling and whether this can be therapeutically reversed remain unknown. The mTOR inhibitor everolimus reduces progerin levels in non-cardiac cells, but its effects in cardiomyocytes have not been examined.
Hypothesis:
We hypothesized that progerin accumulation disrupts cardiomyocyte mechanical and electrical coupling, and that mTOR inhibition restores intercellular connectivity and contractile function.
Approach:
HGPS patient–derived iPSCs carrying the heterozygous LMNA c.1824C>T mutation were differentiated into cardiomyocytes (iPSC-CMs). Cx43 and progerin were assessed by western blotting and immunofluorescence. Gap junction function and synchronicity were evaluated by dye transfer and calcium imaging. Atomic force microscopy assessed cellular stiffness. Cells were treated with everolimus followed by molecular and functional analyses.
Results:
HGPS iPSC-CMs showed progerin accumulation, reduced Cx43 expression, and loss of Cx43 at cell–cell junctions, accompanied by impaired dye transfer, asynchronous calcium transients, and increased stiffness. Everolimus reduced progerin and restored Cx43 in a dose-dependent manner. Importantly, mTOR inhibition rescued gap junction communication and improved calcium transient synchrony, indicating functional restoration of cardiomyocyte coupling.
Conclusion:
Progerin disrupts cardiomyocyte coupling and biomechanics, contributing to dysfunction in HGPS. Everolimus restores gap junction organization and electrical synchrony, identifying a cardiomyocyte-directed therapeutic strategy for HGPS-associated cardiac dysfunction. These findings establish a mechanistic link between nuclear envelope pathology and intercellular communication in human cardiomyocytes.