title: Experimentally increasing titin compliance in a novel mouse model attenuates the Frank-Starling mechanism but has a beneficial effect on diastole.
abstract: BACKGROUND
  Experimentally upregulating compliant titins has been suggested as a therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study. We investigate the effect of upregulating compliant titins in a novel mouse model with a genetically altered titin splicing factor; integrative approaches were used from intact cardiomyocyte mechanics to pressure-volume analysis and Doppler echocardiography.
  
  
  RESULTS
  Compliant titins were upregulated through deletion of the RNA Recognition Motif of the splicing factor RBM20 (Rbm20(ΔRRM)mice). A genome-wide exon expression analysis and a candidate approach revealed that the phenotype is likely to be dominated by greatly increased lengths of titin's spring elements. At both cardiomyocyte and left ventricular chamber levels, diastolic stiffness was reduced in heterozygous (+/-) Rbm20(ΔRRM)mice with a further reduction in homozygous (-/-) mice at only the intact myocyte level. Fibrosis was present in only -/- Rbm20(ΔRRM) hearts. The Frank-Starling Mechanism was reduced in a graded fashion in Rbm20(ΔRRM) mice, at both the cardiomyocyte and left ventricular chamber levels. Exercise tests revealed an increase in exercise capacity in +/- mice.
  
  
  CONCLUSIONS
  Titin is not only important in diastolic but also in systolic cardiac function. Upregulating compliant titins reduces diastolic chamber stiffness owing to the increased compliance of myocytes, but it depresses end-systolic elastance; under conditions of exercise, the beneficial effects on diastolic function dominate. Therapeutic manipulation of the RBM20-based splicing system might be able to minimize effects on fibrosis and systolic function while improving the diastolic function in patients with heart failure.
authors.affiliation: Sarver Molecular Cardiovascular Research Program, Departments of Physiology and Cellular and Molecular Medicine, University of Arizona, Tucson, AZ (M.M., K.R.H., E.-J.L., J.E.S., C.S., C.G.H., C.A.C.O., H.G.); and Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands (C.A.C.O.).
authors.forename: Mei
authors.initials: M
authors.lastname: Methawasin
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Hutchinson
authors.forename: Eun-Jeong
authors.initials: EJ
authors.lastname: Lee
authors.forename: John E
authors.initials: JE
authors.lastname: Smith
authors.forename: Chandra
authors.initials: C
authors.lastname: Saripalli
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Hidalgo
authors.forename: Coen A C
authors.initials: CA
authors.lastname: Ottenheijm
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000502:physiology*; D064211:Connectin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003971:Diastole / Q000502:physiology*; D015150:Echocardiography, Doppler; D004548:Elasticity / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000502:physiology*; D059289:Vascular Stiffness / Q000502:physiology; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: D064211:Connectin
keywords: connectin; diastole; myocardial contraction; myocytes, cardiac; physiology