Abstract
We investigated the effect of the hypertrophic cardiomyopathy-linked R21C (arginine to cysteine) mutation in human cardiac troponin I (cTnI) on the contractile properties and myofilament protein phosphorylation in papillary muscle preparations from left (LV) and right (RV) ventricles of homozygous R21C+/+ knock-in mice. The maximal steady-state force was significantly reduced in skinned papillary muscle strips from the LV compared to RV, with the latter displaying the level of force observed in LV or RV from wild-type (WT) mice. There were no differences in the Ca2+ sensitivity between the RV and LV of R21C+/+ mice; however, the Ca2+ sensitivity of force was higher in RV-R21C+/+ compared with RV-WT and lower in LV- R21C+/+ compared with LV-WT. We also observed partial loss of Ca2+ regulation at low [Ca2+]. In addition, R21C+/+-KI hearts showed no Ser23/24-cTnI phosphorylation compared to LV or RV of WT mice. However, phosphorylation of the myosin regulatory light chain (RLC) was significantly higher in the RV versus LV of R21C+/+ mice and versus LV and RV of WT mice. The difference in RLC phosphorylation between the ventricles of R21C+/+ mice likely contributes to observed differences in contractile force and the lower tension monitored in the LV of HCM mice.
Highlights
The pump function of the heart is achieved by a sequence of alternating contraction and relaxation of the heart muscle
We aimed to examine the effect of the HCMlinked R21C in cardiac troponin I (cTnI) on the function and protein phosphorylation and pinpoint potential differences between the LV and RV using papillary muscle fibers from the KI homozygous mice compared to WT
The R21C mutation was identified in a cardiomyopathy patient, who presented with atrial fibrillation shortly after the sudden death of her child at the age of 18 years [13]
Summary
The pump function of the heart is achieved by a sequence of alternating contraction and relaxation of the heart muscle. Both the left (LV) and right (RV) ventricles contract simultaneously, there are functional and structural differences between them. Several studies using experimental mechanics and computational modeling have proved that the helical geometry of the muscle fibers of the LV changes gradually from right-handed in the subendocardium to left-handed in the subepicardium, which produces a distinctive counter directional movement of the fiber layers in a beating heart [2,3,4,5]. The RV does very little work against gravity. The stroke work for RV is approximately 25% of that for LV because of low resistance of the pulmonary vasculature. The RV is distinguished from the LV by having coarser trabeculae and a lack of fibrous continuity between its inflow and outflow valves [6, 7]
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