Related Experiment Video
Updated: May 22, 2025
Probing Myosin Ensemble Mechanics in Actin Filament Bundles Using Optical Tweezers
Published on: May 4, 2022
Heterogeneous Dysregulation of Myosin Super-Relaxation and Energetics in Hypertrophic Cardiomyopathy
Julien Ochala1,2, Miao Feng3, Qian Wang3
1Department of Biomedical Sciences, University of Copenhagen, Denmark (J.O., C.C., E.E.N., C.T.A.L.).
Insights
Hypertrophic cardiomyopathy variants in MYL2 and TNNI3/TNNT2 genes impact myosin super-relaxation differently, affecting cardiac energetics and response to mavacamten. Variant-specific analysis is crucial for myosin inhibitor therapy.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetic Basis of Heart Disease
Background:
- Hypertrophic cardiomyopathy (HCM) is frequently associated with pathogenic variants in genes encoding myofilament proteins.
- The precise molecular mechanisms driving cardiac dysfunction and metabolic remodeling in HCM due to these variants are not fully understood.
- The myosin super-relaxed state is a key regulator of cardiac energy expenditure, but its modulation by HCM-associated variants is unclear.
Purpose of the Study:
- To investigate whether likely pathogenic and pathogenic variants in thick (MYL2) and thin (TNNI3, TNNT2) filament genes influence the myosin super-relaxed state.
- To elucidate the impact of these variants on cardiac energetics and myosin function in HCM.
Main Methods:
- Cardiac muscle strips were isolated from HCM patients with MYL2, TNNI3, or TNNT2 variants and from non-failing donors.
- Experiments included ATP chase assays using a fluorescent ATP analog, X-ray diffraction, and all-atomistic molecular dynamics simulations.
Main Results:
- HCM-associated variants in MYL2 (thick filament) and TNNI3/TNNT2 (thin filament) genes exhibit opposing effects on cardiac myosin autoinhibition and the super-relaxed state.
- MYL2 variants decreased myosin super-relaxation, while TNNI3/TNNT2 variants promoted an energy-saving 'hibernating' state of myosin heads.
- Thin filament variants impaired the in vitro response to mavacamten, an inhibitor targeting HCM.
Conclusions:
- The myosin super-relaxed state, ATP consumption, and response to mavacamten in HCM are dependent on the specific myofilament variant.
- These findings highlight the importance of considering variant-specific effects when evaluating myosin inhibitors for clinical use in HCM patients.
Background:
Hypertrophic cardiomyopathy is often linked to likely pathogenic and pathogenic variants in genes encoding myofilament proteins. The exact molecular mechanisms by which these lead to cardiac dysfunction and metabolic remodeling remain incompletely understood. Hence, here, we sought to determine whether likely pathogenic and pathogenic variants in thick (MYL2) and thin (TNNI3 or TNNT2) filament genes modulate the myosin super-relaxed state, a critical molecular regulator of heart energetics.
Methods:
We isolated cardiac strips from the septum of 13 patients with hypertrophic cardiomyopathy with MYL2, TNNI3, or TNNT2 gene variants and 10 nonfailing donors. We performed 2'-(or-3')-O-(N-methylanthraniloyl) ATP chase experiments and x-ray diffraction as well as all-atomistic molecular dynamics simulations.
Results:
We observed that, despite preserved myofilament lattice, likely pathogenic and pathogenic variants in thick and thin filament proteins have opposite effects on cardiac myosin autoinhibition and the subsequent proportion of myosin molecules in the ATP-preserving super-relaxed state. As expected, MYL2-associated thick filament variants depressed myosin super-relaxation. However, with TNNI3- or TNNT2-related thin filament variants, myosin heads adopt an energy-saving biochemical hibernating state. Ultimately, these thin filament defects blunted the in vitro response to the hypertrophic cardiomyopathy-targeted inhibitor, mavacamten.
Conclusions:
Our findings indicate that, in hypertrophic cardiomyopathy, cardiac myosin super-relaxed state, associated ATP consumption, and in vitro mavacamten responsiveness depend on the type of myofilament variants. Our data warrant careful analyses of variant-specific responses to myosin inhibitors in the clinic.
More Related Videos
Related Concept Videos
01:29Pathophysiology of Cardiac Performance
01:26Cross-bridge Cycle
01:17Pathophysiology of Heart Failure
01:27Specialized Characteristics of Cardiac Muscles
Cardiac muscle cells are smaller than skeletal muscles, averaging 10–20 mm in diameter and 50–100 mm in length. However, they have large energy demands for continuous contraction and relaxation. This energy is almost exclusively derived from aerobic metabolism of energy...
01:25Smooth Muscle Contraction
The onset of contraction is triggered by an increase in calcium ions within the sarcoplasm, similar to the process in striated muscle. However, smooth muscles have a relatively smaller reservoir of the sarcoplasmic...
01:26Imbalances in Cardiac Output
CHF can occur due to the failure of either side of the heart. Left-side failure leads to pulmonary congestion—the right side continues to send...