Background: Cardiac disease often manifests with sex-specific differences in frequency, pathology, and progression. However, the molecular mechanisms underlying these differences remain incompletely understood. The glycoprotein A1BG has emerged as a female-specific regulator of cardiac structure and integrity, yet its precise role in the female heart is not well characterized.
Methods: To investigate the sex-specific role of A1BG in the heart, we generated both a conditional A1bg knockout allele and an A1bg Rosa26 knockin allele. We employed histological analysis, electrocardiography, RNA sequencing (RNA-seq), transmission electron microscopy (TEM), western blotting, mass spectrometry, and immunohistochemistry to assess structural, functional, and molecular phenotypes.
Results: Loss of A1BG in cardiomyocytes leads to persistent structural remodeling in female, but not male, hearts. Despite preserved systolic function in female A1bgCM/CM mice left ventricular dilation and wall thinning are evident and sustained over time, consistent with early-stage dilated cardiomyopathy (DCM). Transcriptomic analyses reveal that A1BG regulates key metabolic pathways in females, including glucose-6-phosphate and acetyl-CoA metabolism. TEM imaging highlights sex-specific disruption of intercalated disc architecture in female cardiomyocytes. These findings suggest that the absence of A1BG initiates chronic pathological remodeling in female hearts, potentially predisposing them to DCM under stress or aging.
Conclusion: A1BG is essential for maintaining ventricular structural integrity in female, but not male, hearts, leading to a chronic remodeling consistent with early-stage DCM.
Female mice with a mutation in the A1BG gene experience significant heart problems, such as an enlarged left ventricle and thinner heart walls, changes not observed in male mice with the same mutation. Female hearts exhibit different gene activity related to heart function and metabolism than males. The mutation impacts the structure of heart cell connections in females, resulting in impaired heart function and electrical activity, including longer times for the heart’s electrical signals to travel. These defects are similar to those observed in patients with dilated cardiomyopathy. The results indicate that A1BG plays a crucial role in how the female heart forms connections between cells and maintains its structure. The sex-specific requirements for A1BG in the heart could be attributed to the fact that A1BG interacts with different protein partners in male and female hearts. This research highlights the importance of A1BG in maintaining healthy heart function and structure in female mice, suggesting that targeting A1BG could help treat heart disease, especially in women.
© 2025. The Author(s).