Mavacamten enhanced the super-relaxed state of myosin in myofibrils, requiring a tenfold lower concentration to be effective in cardiac and slow-twitch muscle compared to fast-twitch muscle.
Mavacamten enhances the super-relaxed state of myosin more potently in cardiac and slow-twitch myofibrils than in fast-twitch myofibrils, though its efficacy is temperature-dependent.
) using a simple fluorescent ATP chase assay (Hooijman, P. et al (2011) Biophys. J.100, 1969-1976). Studies have normally used purified proteins, myosin filaments, or muscle fibers. Here we use muscle myofibrils, which retain most of the ancillary proteins and 3-D architecture of muscle and can be used with rapid mixing methods. Recording timescales from 0.1 to 1000 s provides a precise measure of the two populations of myosin heads present in relaxed myofibrils. We demonstrate that the population of SRX states is formed from rigor cross bridges within 0.2 s of relaxing with fluorescently labeled ATP, and the population of SRX states is relatively constant over the temperature range of 5 °C-30 °C. The SRX population is enhanced in the presence of mavacamten and reduced in the presence of deoxy-ATP. Compared with myofibrils from fast-twitch muscle, slow-twitch muscle, and cardiac muscles, myofibrils require a tenfold lower concentration of mavacamten to be effective, and mavacamten induced a larger increase in the population of the SRX state. Mavacamten is less effective, however, at stabilizing the SRX state at physiological temperatures than at 5 °C. These assays require small quantities of myofibrils, making them suitable for studies of model organism muscles, human biopsies, or human-derived iPSCs.
Walklate et al. (Tue,) reported a other. Mavacamten and deoxy-ATP was evaluated on Population of super-relaxed (SRX) states. Mavacamten enhanced the super-relaxed state of myosin in myofibrils, requiring a tenfold lower concentration to be effective in cardiac and slow-twitch muscle compared to fast-twitch muscle.