Cardiac Chamber‐Specific Regulation of Myosin Biochemical Super‐Relaxation and Auto‐Inhibition

Mammal atrial and ventricular cardiomyocytes have distinct contractile and energetic properties. Among the molecular processes thought to be involved in such differences is myosin isoform diversity. Our understanding of the related biophysical consequences remains incomplete. Hence, here, utilizing swine isolated cardiac strips and a combination of Mant-ATP (2'-(or-3')-O-(N-Methylanthraniloyl) Adenosine 5'-Triphosphate) chase experiments and all-atomistic molecular dynamics simulations, we aimed to define whether and how chamber-specific myosin isoform specificity influences super-relaxation, critical for heart energetics and contractility. Interestingly, we observed that the proportion of ATP-conserving super-relaxed myosin molecules is greater in porcine ventricles than in atria. We also predicted, through simulations, that such findings were directly related to residues belonging to chamber-specific regulatory light chains differently controlling myosin auto-inhibition. Altogether, we believe that our data should be taken into account when screening for potential myosin-centered compounds for atrial or ventricular myopathies.