Impact of Mavacamten on Force Generation in Single Myofibrils from Rabbit Psoas and Human Cardiac Muscle

Mavacamten (MYK-461, Axon Medchem BV ) is an allosteric inhibitor of sarcomeric myosins presently used in preclinical/clinical trials for HCM treatment (Anderson et al., 2018)). Here, single or thin bundles of myofibrils from rabbit fast skeletal muscle (psoas) and human donor ventricle (frozen samples) have been used to study the effects of mmolar Mavacamten on maximal isometric force. Both myofibril types were mounted in relaxing solution (pCa 9; [Pi] 200 mM , 15 C,) and then fully activated (pCa 4.5) with and without selected concentrations of Mavacamten or subjected to rapid Mavacamten jumps in activating solution. Dose-response curves confirmed a higher sensitivity of maximal isometric force developed by cardiac muscle (IC50 0.5 mM) compared to fast skeletal (IC50 10 mM) as previously reported for pCa50- activated ATPase of the same myofibrillar systems (Kawas et al., 2017). In fast skeletal myofibrils, the kinetics of force development were also strongly depressed by Mavacamten with a trend to a higher sensitivity compared to the effect on tension. This effect was undetectable in human ventricle. When submitted to Mavacamten jumps, both myofibril types responded with a rapid relaxation-like force drop (fully reversible ) whose sensitivity to Mavacamten concentration was the same as that of the kinetics of force relaxation measured in the same conditions. The effect was unaffected by ADP (10 mM) and Pi (0-1 mM range). The results obtained are in agreement with the reported effect of Mavacamten on multiple stages of cross-bridge chemo-mechanical cycle (i.e. inhibition of Pi release rate and decrease of actin binding in M.ADP states) as well as on regulation state mediated by the availability of strongly actin binding heads. SilicoFCM EU H2020 grant agreement n. 777204.