Mavacamten (MYK-461) is a small molecule allosteric inhibitor of sarcomeric myosins being used in preclinical/clinical trials for Hypertrophic Cardiomyopathy treatment. Despite the advancing of clinical studies, very little is known of Mavacamtem action on the mechanics of contraction of mammalian myocardium and fast skeletal muscle, especially in the human cardiac model. To date no information is available regarding the effect of the drug in the human atrium. Moreover, a better understanding of the impact of Mavacamten on force generation in intact or skinned striated muscle preparations, especially for human cardiac muscle, has been hindered by diffusional barriers. These limitations have been overcome by mechanical experiments using myofibrils subjected to perturbations of the contractile environment by sudden solution changes. Here we characterize the action of Mavacamten in atrial myofibrils from human and rat compared to ventricular myofibrils from human donor and fast skeletal myofibrils from rabbit psoas. Mavacamten had a fast, fully reversible, and dose dependent negative effect on maximal Ca2+-activated isometric force at 15º, which can be explained by a sudden decrease in the number of heads functionally available for interaction with actin. Mavacamten strongly depressed the kinetics of force generation of human and rat atrial myofibrils similarly to what had been observed in fast skeletal muscle myofibrils while it had no effect in human ventricular myofibrils. Mavacamten did not alter force relaxation of fast skeletal myofibrils, but it significantly accelerated the relaxation of human ventricular and atrial myofibrils. Mavacamten had no effect on resting tension but inhibited the ADP-stimulated force in the absence of Ca2+. Altogether, these effects outline a motor isoform-specific dependence of the inhibitory effect of Mavacamten on force generation, which is mediated by a reduction in the availability of strongly actin binding heads. Mavacamten may thus alter the interplay between thick and thin filament regulation mechanisms of contraction in association with the widely documented drug effect of stabilizing myosin motor heads into auto-inhibited states. In conclusion, although very promising, Mavacamten as well as the entire class of small molecules acting as inhibitors of sarcomeric myosins, can globally depress cardiac muscle contractility with potential detrimental consequences on the overall cardiac output. The characterization of the effect of Mavacamten described in this work is of great interest for clinical studies assessing the suitability of small molecules for the therapy of Hypertrophic Cardiomyopathy and for the development of new therapeutic approaches.

EFFECTS OF MAVACAMTEN, A FIRST-IN-CLASS INHIBITOR OF SARCOMERIC MYOSINS, ON THE MECHANICS OF ATRIAL AND VENTRICULAR MAMMALIAN MYOCARDIUM AND FAST SKELETAL MUSCLE / Beatrice Scellini, Nicoletta Piroddi , Marica Dente , Giulia Vitale , Josè Manuel Pioner , Raffaele Coppini , Cecilia Ferrantini , Corrado Poggesi , Chiara Tesi. - (2022).

EFFECTS OF MAVACAMTEN, A FIRST-IN-CLASS INHIBITOR OF SARCOMERIC MYOSINS, ON THE MECHANICS OF ATRIAL AND VENTRICULAR MAMMALIAN MYOCARDIUM AND FAST SKELETAL MUSCLE

Beatrice Scellini;Nicoletta Piroddi;Marica Dente;Giulia Vitale;Josè Manuel Pioner;Raffaele Coppini;Cecilia Ferrantini;Corrado Poggesi;Chiara Tesi
Supervision
2022

Abstract

Mavacamten (MYK-461) is a small molecule allosteric inhibitor of sarcomeric myosins being used in preclinical/clinical trials for Hypertrophic Cardiomyopathy treatment. Despite the advancing of clinical studies, very little is known of Mavacamtem action on the mechanics of contraction of mammalian myocardium and fast skeletal muscle, especially in the human cardiac model. To date no information is available regarding the effect of the drug in the human atrium. Moreover, a better understanding of the impact of Mavacamten on force generation in intact or skinned striated muscle preparations, especially for human cardiac muscle, has been hindered by diffusional barriers. These limitations have been overcome by mechanical experiments using myofibrils subjected to perturbations of the contractile environment by sudden solution changes. Here we characterize the action of Mavacamten in atrial myofibrils from human and rat compared to ventricular myofibrils from human donor and fast skeletal myofibrils from rabbit psoas. Mavacamten had a fast, fully reversible, and dose dependent negative effect on maximal Ca2+-activated isometric force at 15º, which can be explained by a sudden decrease in the number of heads functionally available for interaction with actin. Mavacamten strongly depressed the kinetics of force generation of human and rat atrial myofibrils similarly to what had been observed in fast skeletal muscle myofibrils while it had no effect in human ventricular myofibrils. Mavacamten did not alter force relaxation of fast skeletal myofibrils, but it significantly accelerated the relaxation of human ventricular and atrial myofibrils. Mavacamten had no effect on resting tension but inhibited the ADP-stimulated force in the absence of Ca2+. Altogether, these effects outline a motor isoform-specific dependence of the inhibitory effect of Mavacamten on force generation, which is mediated by a reduction in the availability of strongly actin binding heads. Mavacamten may thus alter the interplay between thick and thin filament regulation mechanisms of contraction in association with the widely documented drug effect of stabilizing myosin motor heads into auto-inhibited states. In conclusion, although very promising, Mavacamten as well as the entire class of small molecules acting as inhibitors of sarcomeric myosins, can globally depress cardiac muscle contractility with potential detrimental consequences on the overall cardiac output. The characterization of the effect of Mavacamten described in this work is of great interest for clinical studies assessing the suitability of small molecules for the therapy of Hypertrophic Cardiomyopathy and for the development of new therapeutic approaches.
Prof. Chiara Tesi
ITALIA
Beatrice Scellini, Nicoletta Piroddi , Marica Dente , Giulia Vitale , Josè Manuel Pioner , Raffaele Coppini , Cecilia Ferrantini , Corrado Poggesi , Chiara Tesi
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2158/1275439
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