Key result
The P710R mutation in β-cardiac myosin led to hypercontractility by significantly reducing the proportion of myosin in the super relaxed state to 27% compared to 55-65% in wild-type.
Why the study?
It has been difficult to predict how diverse molecular effects of MYH7 mutations combine to influence cellular forces and phenotypes in hypertrophic cardiomyopathy.
Does the P710R mutation in β-cardiac myosin lead to hypercontractility by disrupting the super relaxed state in human iPSC-derived cardiomyocytes?
Population
Micropatterned hiPSC-cardiomyocytes and isolated myosin constructs
Comparison
CRISPR-edited P710R mutation vs isogenic control
Design
Preclinical in vitro and computational modeling study
Authors
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Supports myosin super-relaxed state disruption as hypercontractility driver in models; leaves open relevance to human hypertrophic cardiomyopathy.
Does the P710R mutation in β-cardiac myosin lead to hypercontractility by disrupting the super relaxed state in human iPSC-derived cardiomyocytes?
Absolute Event Rate: 27% vs 60%
p-value: p=0.0001
The P710R mutation in β-cardiac myosin causes hypercontractility in hypertrophic cardiomyopathy by disrupting the super relaxed state, despite reducing single-molecule step size and load sensitivity.
Roest et al. (2021) studied Hypertrophic cardiomyopathy. P710R mutation in β-cardiac myosin vs. Wild-type β-cardiac myosin was evaluated on Proportion of myosin in the super relaxed state (SRX) for 25-hep constructs (p=0.0001). The P710R mutation in β-cardiac myosin led to hypercontractility by significantly reducing the proportion of myosin in the super relaxed state to 27% compared to 55-65% in wild-type.
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