| Autor: |
Governali, Serena, Caremani, Marco, Gallart, Cristina, Pertici, Irene, Stienen, Ger, Piazzesi, Gabriella, Ottenheijm, Coen, Lombardi, Vincenzo, Linari, Marco |
| Předmět: |
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| Zdroj: |
Nature Communications; 7/7/2020, Vol. 11 Issue 1, p1-12, 12p |
| Abstrakt: |
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. Omecamtiv mecarbil is a small molecule effector under clinical trial for the treatment of systolic heart failure. Here the authors define the molecular mechanisms of its inotropic action and find it can increase the efficiency of contraction in muscle fibres when the orthophosphate concentration rises with the beat frequency. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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