Key result
The P710R mutation in β-cardiac myosin drives hypercontractility and cellular hypertrophy by disrupting the super-relaxed state, freeing more myosin heads to generate force.
Why the study?
It has been difficult to predict how diverse molecular effects of HCM mutations combine to influence cellular forces and phenotypes.
Population
Micropatterned hiPSC-cardiomyocytes CRISPR-edited with the P710R mutation and single myosin molecules
Comparison
P710R mutation vs isogenic control cells
Design
Preclinical in vitro and computational modeling study
Authors
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Suggests myosin super-relaxed state as therapeutic target in genetic cardiomyopathy; leaves open clinical translation pending prospective validation.
Absolute Event Rate: 27% vs 60%
p-value: p=0.0001
The P710R mutation in β-cardiac myosin causes hypercontractility in hypertrophic cardiomyopathy primarily by disrupting the super-relaxed state, providing a mechanistic target for future therapies.
Roest et al. (2020) studied Hypertrophic cardiomyopathy. P710R mutation in β-cardiac myosin vs. Isogenic wild-type (WT) control was evaluated on Proportion of myosin in the super-relaxed (SRX) state (25-hep construct) (p=0.0001). The P710R mutation in β-cardiac myosin drives hypercontractility and cellular hypertrophy by disrupting the super-relaxed state, freeing more myosin heads to generate force.
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