Myotropes unveil two myosin cycles with distinct kinetics and stroke size
- 1Institute of Molecular and Cell Physiology, Hannover Medical School, 30625 Hannover, Germany
Abstract
Cardiac contraction relies on cyclic interactions between myosin II motors and actin filaments, powered by the free energy of ATP turnover. Targeting of this fundamental process has emerged as a promising therapeutic strategy; Mavacamten, a cardiac myosin inhibitor was recently approved for treating obstructive hypertrophic cardiomyopathy whereas omecamtiv mecarbil was developed as a myosin activator for heart failure. Both myotropes bind to the same myosin pocket but their mechanisms of action remain incompletely understood. Here, we investigate these using optical tweezers mechanoenzymology and single-molecule fluorescence-based actomyosin kinetics applied to {beta}-myosin from donor hearts and recombinant human {beta}-myosin subfragment 1. Our findings reveal unexpected layers of complexity. Both mavacamten and omecamtiv mecarbil partially slow the ATP turnover, giving one fast (similar to physiological) and one drug-induced slow ATP turnover cycle at saturating drug concentrations with different rate-limiting steps for the two compounds. In one of the parallel cycles, mavacamten increases stroke size and appreciably delays the power-stroke, allowing direct visualization of a strongly bound pre-power-stroke state. No power-stroke delay is seen in the other cycle, but a reduced stroke size is observed. Our findings uncover a new paradigm in cardiac regulation at the single-molecule level, demonstrating partial inhibition of myosin as a powerful therapeutic strategy.
Related
- Explainable Artificial Intelligence to Unveil Patterns of Antioxidant Peptides for Free Radical Regulation.
- Isolation and lipidomic profiling of neuronal lipid droplets to unveil the lipid landscape of neurodegenerative disorders
- Elucidating the functional domain architecture of ArCS1, a biomineralizing myosin chitin synthase: I. The role of lipids
- Melanophilin, a Myosin Va Adapter Protein, Biases Track Selection of Myosin Va-and Kinesin-1-Transported Liposomes at Actin-Microtubule Intersections In Vitro
- Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores
BibTeX
@misc{berg2026myotropes,
title = {{Myotropes unveil two myosin cycles with distinct kinetics and stroke size}},
author = {A. E. Berg and T. Wang and E. Spahiu and L. P. Velayuthan and M. Norrby and S. Tagerud and C. dos Remedios and T. Kraft and A. Nayak and M. Usaj and A. Mansson and M. Amrute-Nayak},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.11.750962},
url = {https://www.biorxiv.org/content/10.64898/2026.09.11.750962v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Myotropes unveil two myosin cycles with distinct kinetics and stroke size
AU - A. E. Berg
AU - T. Wang
AU - E. Spahiu
AU - L. P. Velayuthan
AU - M. Norrby
AU - S. Tagerud
AU - C. dos Remedios
AU - T. Kraft
AU - A. Nayak
AU - M. Usaj
AU - A. Mansson
AU - M. Amrute-Nayak
PY - 2026
DA - 2026/09/11
PB - bioRxiv
DO - 10.64898/2026.09.11.750962
UR - https://www.biorxiv.org/content/10.64898/2026.09.11.750962v1
AB - Cardiac contraction relies on cyclic interactions between myosin II motors and actin filaments, powered by the free energy of ATP turnover. Targeting of this fundamental process has emerged as a promising therapeutic strategy; Mavacamten, a cardiac myosin inhibitor was recently approved for treating obstructive hypertrophic cardiomyopathy whereas omecamtiv mecarbil was developed as a myosin activator for heart failure. Both myotropes bind to the same myosin pocket but their mechanisms of action remain incompletely understood. Here, we investigate these using optical tweezers mechanoenzymology and single-molecule fluorescence-based actomyosin kinetics applied to {beta}-myosin from donor hearts and recombinant human {beta}-myosin subfragment 1. Our findings reveal unexpected layers of complexity. Both mavacamten and omecamtiv mecarbil partially slow the ATP turnover, giving one fast (similar to physiological) and one drug-induced slow ATP turnover cycle at saturating drug concentrations with different rate-limiting steps for the two compounds. In one of the parallel cycles, mavacamten increases stroke size and appreciably delays the power-stroke, allowing direct visualization of a strongly bound pre-power-stroke state. No power-stroke delay is seen in the other cycle, but a reduced stroke size is observed. Our findings uncover a new paradigm in cardiac regulation at the single-molecule level, demonstrating partial inhibition of myosin as a powerful therapeutic strategy.
ER -