Key result
HCM mutations R403Q and R663H cause hypercontractility by reducing super-relaxed myosin heads by ~67%.
Why the study?
Hypertrophic cardiomyopathy mutations in beta-cardiac myosin and myosin binding protein-C cause cardiac hypercontractility, but the underlying molecular mechanism was not fully understood.
Absolute Event Rate: 14% vs 42%
p-value: p=0.03
The study demonstrates that specific HCM mutations induce hypercontractility by increasing the number of functionally-accessible myosin heads, providing a molecular mechanism for the disease.
Hypertrophic cardiomyopathy (HCM) mutations in ß-cardiac myosin and myosin binding protein-C (MyBP-C) cause hypercontractility of the heart. We show that hypercontractility caused by the HCM myosin mutation R663H cannot be explained by changes in the fundamental parameters such as actin-activated ATPase, intrinsic force, velocity of pure actin or regulated thin filaments, or the pCa50 of the velocity of regulated thin filaments. The same conclusion was made earlier for the HCM myosin mutation R403Q (Nag et al. 2015). Using enzymatic assays for the number of functionally-available heads in purified human ß-cardiac myosin preparations, we provide evidence that both R403Q and R663H HCM myosin mutations cause hypercontractility by increasing the number of functionally-accessible myosin heads. We also demonstrate that the myosin mutation R403Q, but not R663H, ablates the binding of myosin with the C0-C7 fragment of myosin binding protein-C.
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Sarkar et al. (2019) studied Hypertrophic cardiomyopathy. R403Q and R663H mutations in ß-cardiac myosin vs. Wild-type (WT) human ß-cardiac myosin was evaluated on Percentage of myosin heads in the super relaxed state (SRX) (p=0.03). The hypertrophic cardiomyopathy mutations R403Q and R663H cause hypercontractility by releasing myosin heads from a sequestered super relaxed state, increasing the number of functionally-accessible heads.
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