Orthophosphate increases the efficiency of slow muscle-myosin isoform in the presence of omecamtiv mecarbil

Serena Governali, Marco Caremani, Cristina Gallart, Irene Pertici, Ger Stienen, Gabriella Piazzesi, Coen Ottenheijm, Vincenzo Lombardi () and Marco Linari
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Serena Governali: University of Florence
Marco Caremani: University of Florence
Cristina Gallart: University of Florence
Irene Pertici: University of Florence
Ger Stienen: Amsterdam UMC (location VUmc)
Gabriella Piazzesi: University of Florence
Coen Ottenheijm: Amsterdam UMC (location VUmc)
Vincenzo Lombardi: University of Florence
Marco Linari: University of Florence

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Omecamtiv mecarbil (OM) is a putative positive inotropic tool for treatment of systolic heart dysfunction, based on the finding that in vivo it increases the ejection fraction and in vitro it prolongs the actin-bond life time of the cardiac and slow-skeletal muscle isoforms of myosin. OM action in situ, however, is still poorly understood as the enhanced Ca2+-sensitivity of the myofilaments is at odds with the reduction of force and rate of force development observed at saturating Ca2+. Here we show, by combining fast sarcomere-level mechanics and ATPase measurements in single slow demembranated fibres from rabbit soleus, that the depressant effect of OM on the force per attached motor is reversed, without effect on the ATPase rate, by physiological concentrations of inorganic phosphate (Pi) (1-10 mM). This mechanism could underpin an energetically efficient reduction of systolic tension cost in OM-treated patients, whenever [Pi] increases with heart-beat frequency.

Date: 2020
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DOI: 10.1038/s41467-020-17143-2

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