Early Subclinical and Sex-Specific Cardiac Remodeling Precedes Heart Failure in Zebrafish with Human Actin T126I Mutation

Dilated cardiomyopathy (DCM) is a leading cause of heart failure with notable sex differences in disease susceptibility and progression. Mutations in sarcomeric proteins such as cardiac actin (ACTC1) contribute to familial DCM, yet the in vivo consequences of the ACTC1 p.T126I variant and its sex-specific effects remain unclear. We generated a zebrafish model carrying the orthologous Acta1b p.T126I mutation and conducted longitudinal analyses of cardiac phenotype, function, morphology, and gene expression stratified by sex. Mutants showed variable onset of cardiac dysfunction; surviving adults developed progressive DCM characterized by pericardial effusion, ventricular dilation, and reduced survival. Female mutants exhibited earlier and sustained diastolic dysfunction, more severe cardiac remodeling and significantly lower survival compared to males, revealing pronounced sexual dimorphism. Molecular profiling identified upregulation of the cardiac stress marker nppb , downregulation of hypertrophic transcription factors ( gata4, mef2ca ), stable or reduced sarcomeric gene expression, and sex-specific alterations in calcium handling genes ( serca2, pln1, slc8a1a ) and proteostasis regulators ( hsf1, bag3 ). These findings demonstrate that the Acta1b p.T126I thin filament mutation drives progressive, sex-specific dilated cardiomyopathy in zebrafish, underscoring biological sex as a critical modifier of sarcomeric cardiomyopathy progression and providing a valuable platform for investigating sex-dependent mechanisms and developing targeted therapies relevant to women’s cardiovascular health.