Omecamtiv Mecarbil, a Cardiac Myosin Activator, Increases Ca2+ Sensitivity in Myofilaments With a XXXX Mutant Tropomyosin @entity49819 .

@entity712 @entity308 @entity19 @entity384 @entity49819 @entity460 @entity943 @entity9495 @entity28653
UNASSIGNED: Apart from transplant, there are no satisfactory therapies for the severe @entity308 in contractility in @entity384 ( @entity384 ). Current @entity712 treatments that act by increasing contractility involve signaling cascades that alter @entity460 homeostasis and induce @entity943 . Omecamtiv mecarbil is a promising new inotropic agent developed for @entity712 that may circumvent such limitations. Omecamtiv is a direct cardiac myosin activator that promotes and prolongs the strong myosin-actin binding conformation to increase the duration of systolic elastance. We tested the effect of omecamtiv on @entity9495 sensitivity of myofilaments of a @entity384 @entity19 model containing a tropomyosin @entity49819 mutation. We compared tension and @entity28653 activity of detergent-extracted myofilaments with and without treatment with 316 nM omecamtiv at varying pCa values. When transgenic myofilaments were treated with omecamtiv, the pCa50 for activation of tension increased from 5.70    0.02 to 5.82    0.02 and @entity28653 activity increased from 5.73    0.06 to 6.07    0.04. This significant leftward shift restored @entity9495 sensitivity to levels no longer significantly different from controls. Proteomic studies lacked changes in sarcomeric protein phosphorylation. Our data demonstrate that omecamtiv can potentially augment cardiac contractility in @entity384 by increasing @entity9495 sensitivity. The use of direct myosin activators addresses functional defects without incurring the adverse side effects of @entity9495 -dependent treatments.
