title: The R21C Mutation in Cardiac Troponin I Imposes Differences in Contractile Force Generation between the Left and Right Ventricles of Knock-In Mice.
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 Ca(2+) sensitivity between the RV and LV of R21C(+/+) mice; however, the Ca(2+) 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 Ca(2+) regulation at low [Ca(2+)]. 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.
authors.affiliation: Department of Molecular & Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Molecular & Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kazmierczak
authors.affiliation: Department of Molecular & Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Rojas
authors.affiliation: Department of Molecular & Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Yingcai
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular & Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Danuta
authors.identifier: 0000-0002-8441-0722
authors.initials: D
authors.lastname: Szczesna-Cordary
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D055879:Gene Knock-In Techniques; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D051379:Mice; D009154:Mutation; D009200:Myocardial Contraction / Q000235:genetics*; D009210:Myofibrils / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018994:Myosin Light Chains / Q000378:metabolism; D010210:Papillary Muscles / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D019210:Troponin I / Q000235:genetics* / Q000378:metabolism
chemical_list: D018994:Myosin Light Chains; D019210:Troponin I; D002118:Calcium