Internal medicine

Receptor

Myocyte

Heart failure

Sarcomere

Myosin light-chain kinase

Biology

Gene

Biophysics

Allosteric regulation

Cardiomyopathy

Hypertrophic cardiomyopathy

Mutation

Myosin

MYH7

Missense mutation

Cell biology

Biochemistry

Medicine

Circulation

Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations.

Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy