Early pre-symptomatic and sex-specific cardiac remodeling precedes heart failure in zebrafish with human actin mutation

Dilated cardiomyopathy (DCM) is a leading cause of heart failure with notable sex differences in susceptibility and progression. Although sarcomere mutations such as cardiac actin ACTC1 p.T126I contribute to familial DCM, the in vivo effects and sex-specific consequences remain unclear. We generated a zebrafish model carrying the orthologous Acta1b p.T126I mutation and conducted longitudinal, sex-stratified analyses of cardiac function, morphology and gene expression. Mutants showed variable onset of cardiac dysfunction, with progressive DCM, pericardial effusion, ventricular dilation, and reduced survival in adults. Female mutants exhibited earlier and sustained diastolic dysfunction, greater cardiac remodeling and significantly lower survival compared to males, revealing pronounced sexual dimorphism. Molecular profiling at a pre-symptomatic stage identified upregulation of nppb, downregulation of hypertrophic transcription factors (gata4, mef2ca), and sex-specific alterations in calcium handling genes (serca2, pln1, slc8a1a) and proteostasis regulators (hsf1, bag3). Older stages demonstrated a variable shift of individuals’ gene expression to cardiac remodeling and decompensation. These findings demonstrate that the Acta1b p.T126I mutation drives progressive, sex-specific DCM in zebrafish, highlighting biological sex as a critical modifier of sarcomeric cardiomyopathy progression and targeted therapy development.