title: Early sensitization of myofilaments to Ca2+ prevents genetically linked dilated cardiomyopathy in mice.
abstract: BACKGROUND
  Dilated cardiomoypathies (DCM) are a heterogeneous group of inherited and acquired diseases characterized by decreased contractility and enlargement of cardiac chambers and a major cause of morbidity and mortality. Mice with Glu54Lys mutation in α-tropomyosin (Tm54) demonstrate typical DCM phenotype with reduced myofilament Ca2+ sensitivity. We tested the hypothesis that early sensitization of the myofilaments to Ca2+ in DCM can prevent the DCM phenotype.
  
  
  RESULTS
  To sensitize Tm54 myofilaments, we used a genetic approach and crossbred Tm54 mice with mice expressing slow skeletal troponin I (ssTnI) that sensitizes myofilaments to Ca2+. Four groups of mice were used: non-transgenic (NTG), Tm54, ssTnI and Tm54/ssTnI (DTG). Systolic function was significantly reduced in the Tm54 mice compared to NTG, but restored in DTG mice. Tm54 mice also showed increased diastolic LV dimensions and HW/BW ratios, when compared to NTG, which were improved in the DTG group. β-myosin heavy chain expression was increased in the Tm54 animals compared to NTG and was partially restored in DTG group. Analysis by 2D-DIGE indicated a significant decrease in two phosphorylated spots of cardiac troponin I (cTnI) in the DTG animals compared to NTG and Tm54. Analysis by 2D-DIGE also indicated no significant changes in troponin T, regulatory light chain, myosin binding protein C and tropomyosin phosphorylation.
  
  
  CONCLUSIONS
  Our data indicate that decreased myofilament Ca2+ sensitivity is an essential element in the pathophysiology of thin filament linked DCM. Sensitization of myofilaments to Ca2+ in the early stage of DCM may be a useful therapeutic strategy in thin filament linked DCM.
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, 835 S Wolcott Ave. (M/C 901), Chicago, IL 60612, USA.|Center for Research in Echocardiography and Cardiology, Heart Institute, University of Sao Paulo, Avenida Dr. Eneas de Carvalho Aguiar 44, 05403-900, Sao Paulo, Brazil.
authors.forename: Marco L
authors.initials: ML
authors.lastname: Alves
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, 835 S Wolcott Ave. (M/C 901), Chicago, IL 60612, USA.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Warren
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, 835 S Wolcott Ave. (M/C 901), Chicago, IL 60612, USA.
authors.forename: Jillian N
authors.initials: JN
authors.lastname: Simon
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, 835 S Wolcott Ave. (M/C 901), Chicago, IL 60612, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gaffin
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, 835 S Wolcott Ave. (M/C 901), Chicago, IL 60612, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Montminy
authors.affiliation: Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Wieczorek
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, 835 S Wolcott Ave. (M/C 901), Chicago, IL 60612, USA.
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.affiliation: Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, 835 S Wolcott Ave. (M/C 901), Chicago, IL 60612, USA.|Department of Medicine, Division of Cardiology, University of Illinois, 840 S Wood St. (M/C 715), Chicago, IL 60612, USA.
authors.forename: Beata M
authors.initials: BM
authors.lastname: Wolska
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D014335:Tropomyosin / Q000378:metabolism; D024723:Ventricular Myosins / Q000235:genetics
chemical_list: D014335:Tropomyosin; D017868:Cyclic AMP-Dependent Protein Kinases; D024723:Ventricular Myosins; D002118:Calcium
keywords: DCM; Myofilament Ca2+ sensitivity; New therapy