Sex-specific response to A1BG loss results in female dilated cardiomyopathy
Abstract 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 struc...
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| Format: | Article |
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BMC
2025-04-01
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| Series: | Biology of Sex Differences |
| Online Access: | https://doi.org/10.1186/s13293-025-00713-8 |
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| author | James I. Emerson Wei Shi Frank L. Conlon |
| author_facet | James I. Emerson Wei Shi Frank L. Conlon |
| author_sort | James I. Emerson |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-b84d8360b6ba41cc9ab03e7c4e5f1f78 |
| institution | OA Journals |
| issn | 2042-6410 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Biology of Sex Differences |
| spelling | doaj-art-b84d8360b6ba41cc9ab03e7c4e5f1f782025-08-20T02:30:14ZengBMCBiology of Sex Differences2042-64102025-04-0116111410.1186/s13293-025-00713-8Sex-specific response to A1BG loss results in female dilated cardiomyopathyJames I. Emerson0Wei Shi1Frank L. Conlon2Departments of Biology and Genetics, University of North Carolina at Chapel HillDepartments of Biology and Genetics, University of North Carolina at Chapel HillDepartments of Biology and Genetics, University of North Carolina at Chapel HillAbstract 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.https://doi.org/10.1186/s13293-025-00713-8 |
| spellingShingle | James I. Emerson Wei Shi Frank L. Conlon Sex-specific response to A1BG loss results in female dilated cardiomyopathy Biology of Sex Differences |
| title | Sex-specific response to A1BG loss results in female dilated cardiomyopathy |
| title_full | Sex-specific response to A1BG loss results in female dilated cardiomyopathy |
| title_fullStr | Sex-specific response to A1BG loss results in female dilated cardiomyopathy |
| title_full_unstemmed | Sex-specific response to A1BG loss results in female dilated cardiomyopathy |
| title_short | Sex-specific response to A1BG loss results in female dilated cardiomyopathy |
| title_sort | sex specific response to a1bg loss results in female dilated cardiomyopathy |
| url | https://doi.org/10.1186/s13293-025-00713-8 |
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