Molecular basis of force-pCa relation in MYL2 cardiomyopathy mice: Role of the super-relaxed state of myosin

Abstract

Significance Many forms of cardiomyopathy manifest with changes in sarcomeric structure, function, and energetics. We used small-angle X-ray diffraction and myosin super-relaxed (SRX) state approaches to investigate the mechanisms underlying the clinical phenotypes associated with HCM-related D166V (aspartate-to-valine) and DCM-linked D94A (aspartate-to-alanine) mutations in the cardiac myosin RLC ( MYL2 gene). Modulation of myosin function through dysregulation of the SRX state was closely coupled with structural rearrangements and the Ca 2+ dependence of force development in HCM–D166V mice. The DCM–D94A model favored the SRX state without altering structure/force–pCa relationships. Understanding the regulation of SRX ↔ DRX equilibrium in the normal heart and how it is changed in heart disease may advance future therapeutics of patients suffering from the mutated MYL2 gene.