February 17, 2022Proceedings of the National Academy of Sciences38 citationsOpen Access
Molecular basis of force-pCa relation in MYL2 cardiomyopathy mice: Role of the super-relaxed state of myosin
Structured PICO
P
Population
~5- to 8-month-old male and female mice expressing human ventricular D166V RLC mutant (HCM model), D94A RLC mutant (DCM model), and human nonmutated WT-RLC
I
Intervention
HCM-D166V and DCM-D94A mutations in the MYL2 gene
C
Comparator
Age-matched wild-type (WT) mice
O
Outcome
Ca2+-dependent structure-function relationship (interfilament lattice spacing, equatorial intensity ratios) and myosin energetic states (SRX vs DRX)surrogate
The HCM-D166V mutation increases calcium sensitivity and disrupts the energy-conserving super-relaxed state of myosin, contributing to hypercontractility, providing a molecular mechanism for MYL2-related hypertrophic cardiomyopathy.
Abstract
activation. The HCM-D166V model also disrupted the SRX state and promoted an SRX-to-DRX (super-relaxed to disordered relaxed) transition that correlated with an HCM-linked phenotype of hypercontractility. While this dysregulation of SRX ↔ DRX equilibrium was consistent with repositioning of myosin motors closer to the thin filaments and with increased force-pCa dependence for HCM-D166V, the DCM-D94A model favored the energy-conserving SRX state, but the structure/function-pCa data were similar to WT. Our results suggest that the mutation-induced redistribution of myosin energetic states is one of the key mechanisms contributing to the development of complex clinical phenotypes associated with human HCM-D166V and DCM-D94A mutations.