Increasing the calcium sensitivity of muscle using trifluoperazine-induced manipulations in silico, in vitro and in vivo systems

Many therapeutics for cardiomyopathy treat the symptoms of the disease rather than the underlying mechanism. The mechanism of cardiomyopathy onset is believed to include two means: calcium sensitivity changes and myosin activity alteration. Trifluoperazine is a compound that binds troponin, and other components of the calcium pathway, which impacts calcium regulation of contraction. Here, the ability of TFP to shift calcium sensitivity was examined in vitro with purified proteins and the impact of TFP on heart function was assessed in vivo using embryonic zebrafish. The binding of TFP to troponin was modeled in silico and a model of zebrafish troponin was generated. TFP increased regulated cardiac actomyosin activity in vitro and elevated embryonic zebrafish heart rates at effective drug concentrations. Troponin structural changes predicted in silico suggest altered protein interactions within thin filaments that would affect the regulation of heart function. [Display omitted] •TFP increased the actomyosin activity of thin filaments in vitro.•Zebrafish embryos treated with 2.5 μM TFP had increased heart rates at 72 and 120 hpf.•TFP binding caused structural changes in troponin C and I in silico.•Our novel model of zebrafish troponin behaves similarly to human troponin in silico.