Loss of Elmsan1 in Cardiomyocytes Leads to Age-Dependent Cardiac Dysfunction and Reduced Lifespan

Histone deacetylase (HDAC) complexes regulate pathological gene programs during heart disease progression. The recently identified mitotic deacetylase complex (MiDAC), which includes DNTTIP1, ELMSAN1, and HDAC1/2, remains the least characterized among these complexes. ELMSAN1 has been implicated in left ventricular remodeling, and its global deletion in mice leads to heart malformation. To investigate its role in mouse heart, we generated cardiomyocyte-specific Elmsan1 knockout (ELM cKO) using αMHC driven Cre recombinase. We analyzed both male and female animals across three experimental groups: αMHC-Cre (Cre control), ELM fl/fl (floxed control) and ELM cKO. In male ELM cKO mice, ejection fraction (EF) was significantly reduced by 12 weeks (45.64±3.12%), compared to αMHC-Cre (55.91±1.29%) and ELM fl/fl (59.16±3.70%) controls. By 24 weeks, EF declined further to 20.79%±4.52, representing a reduction of 46.4% (p<0.01) and 62.1% (p<0.0001) compared to αMHC-Cre and ELM fl/fl mice respectively. The heart failure phenotype in ELM cKO mice was supported by cardiomyocyte hypertrophy morphology, ventricular dilation, and shortened lifespan. Female ELM cKO mice exhibited similar defects with delayed onset. To investigate early molecular changes, we performed RNA sequencing on pre-symptomatic hearts from 8-week-old mice. A total of 1055 genes were differentially expressed in ELM ckO hearts, with 460 upregulated and 595 downregulated. Gene enrichment analysis revealed suppression of tricarboxylic acid cycle and key cardiac genes. These transcriptional changes were accompanied by decreased mitochondrial respiratory chain complex proteins, ultrastructural mitochondrial abnormalities, and impaired calcium handling. Our study demonstrates that Elmsan1 is pivotal for maintaining the heart function and hemostasis with advanced age.