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

Dilated cardiomyopathy (DCM) is a leading cause of heart failure with notable sex differences in susceptibility and progression. Although mutations within the sarcomere, such as the change of threonine (T) to isoleucine (I) at position 126 of actin alpha cardiac muscle 1 (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 Ca2+-handling genes (serca2, pln1, slc8a1a) and proteostasis regulators (hsf1, bag3). Assessment at later stages demonstrated a variable shift of gene expression to cardiac remodeling and decompensation in individual fish. These findings demonstrate that the Acta1b p.T126I mutation drives progressive sex-specific DCM in zebrafish, highlighting the biological sex as a critical modifier of sarcomeric cardiomyopathy progression and targeted therapy development.