Hypertrophic cardiomyopathy (HCM) is typically caused by gene mutations that alter proteins in the sarcomere, the contractile apparatus of the heart, with loss-of-function mutations in MYBPC3 (which encodes cardiac myosin binding protein C; cMyBPC) and missense mutations in MYH7 (which encodes myosin heavy chain 7) accounting for >85% of genetic causes of this condition. However, the precise mechanisms by which these mutations lead to the cardiac hypercontractility and poor relaxation that are characteristic of HCM are unclear. A new study published in Science Translational Medicine now shows that MYBPC3 mutations cause increased contractility, reduced relaxation and excessive energy consumption of cardiac muscle by disrupting normal myosin conformations. “Our findings define a fundamental mechanism by which hearts relax and demonstrate that HCM-associated mutations in MYBPC3 cause disease by limiting normal relaxation,” remarks Christopher Toepfer, first author on the paper.

Credit: V. Summersby/Springer Nature Limited

Myosin is the molecular motor of the sarcomere, whereas cMyBPC is thought to act as the molecular brake. Using mouse models and human muscle fibres engineered to contain MYBPC3 mutations associated with HCM in humans, as well as a biochemical assay to assess myosin activity and ATP consumption, Toepfer and colleagues found that mutations in MYBPC3 reduced the amount of cMyBPC in the sarcomeres, which resulted in increased myosin contractility. The severity of cardiomyocyte phenotypes was dependent on the quantity of cMyBPC in the sarcomeres. Genetic repression of myosin motor function in mice that were engineered to carry a human MYH7 mutation improved the hypercontractile phenotype caused by cMyBPC deficiency, suggesting myosin dysregulation as the underlying mechanism in the pathogenicity of cMyBPC depletion. Furthermore, MYBPC3 mutations also impaired myosin functions during relaxation by destabilizing the myosin super-relaxed conformation — a state of dual inactivation of myosins with both ATPases inhibited, which is associated with energy conservation — and promoting a more active state that enables ATP hydrolysis and thin filament interactions.

Finally, Toepfer and colleagues demonstrated that a single pharmacological treatment targeting myosin function can correct the sarcomere dysfunction caused by MYBPC3 mutations. The myosin ATPase inhibitor MYK-461, which is in clinical trials for the treatment of HCM, normalized the contraction and relaxation, as well as the alterations in myosin conformation, in mouse and human cardiomyocytes with MYBPC3 mutations. “The study shows a promising approach to fix the basic abnormality in HCM: target the molecular motor with drugs that reduce excessive contraction and improve relaxation,” highlights Toepfer. “This potential treatment would enable the first precision medicine in HCM that directly addresses the molecular mechanism of disease, not just symptoms,” he adds.