# Sex-specific response to A1BG loss results in female dilated cardiomyopathy

## TL;DR

Loss of A1BG in female hearts causes structural changes linked to early-stage dilated cardiomyopathy, but not in males.

## Contribution

A1BG is identified as a female-specific regulator of heart structure, with its loss causing sex-specific cardiac remodeling.

## Key findings

- A1BG loss in female cardiomyocytes leads to left ventricular dilation and wall thinning consistent with early-stage DCM.
- A1BG regulates sex-specific metabolic pathways, including glucose-6-phosphate and acetyl-CoA metabolism in females.
- Intercalated disc architecture is disrupted in female cardiomyocytes, and A1BG interacts with sex-specific protein networks.

## Abstract

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.

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.

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.

A1BG is essential for maintaining ventricular structural integrity in female, but not male, hearts, leading to a chronic remodeling consistent with early-stage DCM.

The online version contains supplementary material available at 10.1186/s13293-025-00713-8.

Female mice but not male mice with a cardiac muscle-specific conditional loss-of-function mutation in A1BG exhibit significant cardiac dysfunction indicative of dilated cardiomyopathy.

Female and male cardiomyocyte A1BG null hearts showed different gene expression patterns, indicating that the cardiac metabolic adaptations required in the absence of A1BG are sex specific.

Functional network analyses of the cardiac interactomes of female and male A1BG reveal that A1BG interacts with different sets of proteins based on sex, suggesting that these interactions are crucial for the sex-specific roles of A1BG in cardiac function and dilated cardiomyopathy.

The online version contains supplementary material available at 10.1186/s13293-025-00713-8.