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- W4387615352 abstract "Actin is conserved in all eukaryotic cells with six isoforms in humans. Skeletal muscle actin (ACTA1) is the primarily expressed isoform in skeletal muscle; however, it is also expressed at low levels in the heart. ACTA1 mutations are well known to cause skeletal myopathy, but mechanistic insights are incomplete due to difficulties with generating recombinant protein and limited in vivo modeling. The impact of ACTA1 mutations on cardiac function is controversial. We previously reported a novel missense heterozygous mutation in ACTA1, R256H, associated with dilated cardiomyopathy (DCM) without overt skeletal myopathy in patients. The objective of this study was to define the mechanistic basis by which ACTA1 R256H contributes to DCM. To establish the pathogenicity of ACTA1 R256H, we generated Acta1 R256H mice. Acta1 R256H/R256H mice display perinatal mortality. We also observed reduced survival and gross phenotypes in Acta1 R256H/+ mice over time. To further characterize ACTA1 R256H in human cardiomyocytes, we generated ACTA1 R256H/+ human induced pluripotent stem cells which we differentiated into cardiomyocytes. ACTA1 R256H/+ cardiomyocytes generated less force and displayed aberrant sarcomere structure compared to isogenic controls. To biochemically define the consequences of ACTA1 R256H protein, we developed a novel method to generate recombinant wildtype ACTA1 and ACTA1 R256H. Strikingly, ACTA1 R256H demonstrated severely reduced polymerization kinetics possibly accounting for the observed disruption in sarcomere structure. This finding was further supported by molecular dynamic simulations which identified impaired nucleotide binding in ACTA1 R256H compared to wildtype ACTA1 protein. Together, these findings reveal that a mutation in skeletal muscle actin results in increased mortality, cardiomyocyte hypocontractility, sarcomeric disruption, and impaired actin polymerization. Our work defines a cardiac function for skeletal muscle actin and establishes a multiscale approach to studying cardiomyopathy-associated actin mutations." @default.
- W4387615352 created "2023-10-14" @default.
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- W4387615352 date "2023-08-04" @default.
- W4387615352 modified "2023-10-15" @default.
- W4387615352 title "Abstract EC.06: Skeletal Muscle Actin Mutation R256H Disrupts Actin Polymerization And Cardiomyocyte Contractility: A Multi-scale Study Of Genetic Dilated Cardiomyopathy" @default.
- W4387615352 doi "https://doi.org/10.1161/res.133.suppl_1.ec.06" @default.
- W4387615352 hasPublicationYear "2023" @default.
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