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Abstract

Cardiomyocytes depend on tightly regulated gene networks for development, maturation, and function. Disruption of these networks can cause cardiomyopathies, such as hypertrophic or dilated forms, often leading to heart failure. RNA-binding protein Cpeb4 was previously identified as a dynamic regulator in cardiac hypertrophy and found Zinc Finger E-Box Binding Homeobox 1 (Zeb1) acting downstream. While Zeb1 is known for roles in cancer metastasis and epithelial-to-mesenchymal transition, its function in heart muscle remained unclear. Given its importance in skeletal muscle regeneration, it was hypothesized that Zeb1 supports cardiomyocyte development, structural stability, and contractile performance. To test this, I used AAV9-Zeb1 to overexpress Zeb1 in 8-week-old mice. Elevated Zeb1 promoted maladaptive hypertrophy and impaired cardiac function, indicating that excessive Zeb1 is harmful. Complementary loss-of-function studies employed a cardiomyocyte-specific Zeb1 conditional knockout (Zeb1 cKO) via αMHC-Cre. By 12 weeks, cKO mice showed early systolic dysfunction, which worsened with age. At 25 weeks, histology and electron microscopy revealed sarcomeric disorganization and abnormal mitochondria. Female cKO mice were more severely affected than males, suggesting sex-specific dependence on Zeb1. A tamoxifen-inducible knockout (Zeb1 icKO) model, deleting Zeb1 after full maturation, showed that only females experienced a significant decline in ejection fraction, reinforcing Zeb1’s role in long-term cardiac maintenance, particularly in females. RNA-seq from Zeb1 KO hearts revealed epithelial-like gene expression patterns, implying cytoskeletal and structural changes. In summary, Zeb1 is essential for cardiomyocyte integrity and contractility. Its loss disrupts sarcomeres and accelerates heart failure, especially in females, likely through transcriptional reprogramming. Conversely, Zeb1 overexpression drives pathological hypertrophy, underscoring the need for precise regulation in cardiac homeostasis and disease.