Sex-Specific Response to A1BG Loss Results in Female Dilated Cardiomyopathy

TL;DR

A1BG is essential for female heart function, and its loss causes dilated cardiomyopathy in females but not males.

Contribution

The study reveals a sex-specific role of A1BG in maintaining cardiac structure and function in females.

Findings

A1BG loss causes dilated cardiomyopathy in female mice but not in males.

Female hearts show altered gene activity and structural changes linked to heart function and metabolism.

A1BG interacts with sex-specific protein partners, affecting heart cell connections in females.

Abstract

Cardiac disease often manifests differently in terms of frequency and pathology between men and women. However, the mechanisms underlying these differences are not fully understood. The glycoprotein A1BG is necessary for proper cardiac function in females but not males. Despite this, the role of A1BG in the female heart remains poorly studied.

To determine the sex differential function of A1BG, we generated a novel conditional A1bg allele and a novel conditional A1bg Rosa26 knockin allele. Histology, electrocardiography, transcriptional profiling (RNA-seq), transmission electron microscopy, western blot analyses, mass spectrometry, and immunohistochemistry were used to assess cardiac structure and function.

The study reveals that the absence of A1BG results in significant cardiac dysfunction in female but not male mice. Gene expression underscores that A1BG plays a critical role in metabolic processes and the integrity of intercalated discs in female cardiomyocytes. This dysfunction may be related to sex-specific A1BG cardiac interactomes and manifests as structural and functional alterations in the left ventricle indicative of dilated cardiomyopathy, thus suggesting a sex-specific requirement for A1BG in cardiac health.

The loss of A1BG in cardiomyocytes leads to dilated cardiomyopathy in females, not males.

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.

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