Heterogeneous Dysregulation of Myosin Super-Relaxation and Energetics in Hypertrophic Cardiomyopathy.

BACKGROUND

Hypertrophic cardiomyopathy is often linked to likely pathogenic and pathogenic variants in genes encoding myofilament proteins. The exact molecular mechanisms by which these lead to cardiac dysfunction and metabolic remodeling remain incompletely understood. Hence, here, we sought to determine whether likely pathogenic and pathogenic variants in thick () and thin ( or ) filament genes modulate the myosin super-relaxed state, a critical molecular regulator of heart energetics.

METHODS

We isolated cardiac strips from the septum of 13 patients with hypertrophic cardiomyopathy with , , or gene variants and 10 nonfailing donors. We performed 2'-(or-3')--(-methylanthraniloyl) ATP chase experiments and X-ray diffraction as well as all-atomistic molecular dynamics simulations.

RESULTS

We observed that, despite preserved myofilament lattice, likely pathogenic and pathogenic variants in thick and thin filament proteins have opposite effects on cardiac myosin autoinhibition and the subsequent proportion of myosin molecules in the ATP-preserving super-relaxed state. As expected, -associated thick filament variants depressed myosin super-relaxation. However, with - or -related thin filament variants, myosin heads adopt an energy-saving biochemical hibernating state. Ultimately, these thin filament defects blunted the in vitro response to the hypertrophic cardiomyopathy-targeted inhibitor, mavacamten.

CONCLUSIONS

Our findings indicate that, in hypertrophic cardiomyopathy, cardiac myosin super-relaxed state, associated ATP consumption, and in vitro mavacamten responsiveness depend on the type of myofilament variants. Our data warrant careful analyses of variant-specific responses to myosin inhibitors in the clinic.