Abstract
Dilated cardiomyopathy (DCM) is a naturally occurring heart failure condition in humans and dogs, notably characterized by a reduced ejection fraction. As the identification of the underlying cellular and molecular mechanisms remain incomplete, the aim of the present study was to assess whether myosin and its known relaxed conformational states contribute to DCM aetiology. For that, we dissected and skinned thin cardiac strips from left ventricle obtained from six DCM Doberman Pinschers and six nonfailing controls (NF). We then used Mant-ATP chase experiments, X-ray diffraction and molecular simulations. We observed that, in DCM dogs, the amount of myosin heads in the stabilizing conformational state also known as super-relaxed (SRX) is significantly increased when compared with NF dogs. We also found that myosin heads are blocked in this SRX state preventing a proper length dependent activation, subsequently hindering myosin head recruitment and force-generating capacity. Despite these, our data also demonstrate that when applying EMD-57033, a small molecule activating myosin, SRX-related detrimental effects can be rescued. Taken together, our results suggest that myosin SRX contributes to the DCM pathophysiology and that the observed negative changes are reversible, giving hope for a myosin-centered pharmacological treatment of this particular cardiac disease.
Highlights
The proportion of cardiac myosin heads in the super-relaxed state is greater in left ventricles of Doberman Pinschers with dilated cardiomyopathy than in non-failing dogs.
The length dependent activation of myosin heads is prevented disrupting force generation.
A small molecule known to activate myosin (EMD-57033) partially counterbalances the super-relaxed state disturbance.
Competing Interest Statement
The authors have declared no competing interest.
