title: Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform.
abstract: BACKGROUND
  Tropomyosin (TM), an essential actin-binding protein, is central to the control of calcium-regulated striated muscle contraction. Although TPM1alpha (also called alpha-TM) is the predominant TM isoform in human hearts, the precise TM isoform composition remains unclear.
  
  
  RESULTS
  In this study, we quantified for the first time the levels of striated muscle TM isoforms in human heart, including a novel isoform called TPM1kappa. By developing a TPM1kappa-specific antibody, we found that the TPM1kappa protein is expressed and incorporated into organized myofibrils in hearts and that its level is increased in human dilated cardiomyopathy and heart failure. To investigate the role of TPM1kappa in sarcomeric function, we generated transgenic mice overexpressing cardiac-specific TPM1kappa. Incorporation of increased levels of TPM1kappa protein in myofilaments leads to dilated cardiomyopathy. Physiological alterations include decreased fractional shortening, systolic and diastolic dysfunction, and decreased myofilament calcium sensitivity with no change in maximum developed tension. Additional biophysical studies demonstrate less structural stability and weaker actin-binding affinity of TPM1kappa compared with TPM1alpha.
  
  
  CONCLUSIONS
  This functional analysis of TPM1kappa provides a possible mechanism for the consequences of the TM isoform switch observed in dilated cardiomyopathy and heart failure patients.
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati Medical Center, Cincinnati, OH 45267-0524, USA.
authors.forename: Sudarsan
authors.initials: S
authors.lastname: Rajan
authors.forename: Ganapathy
authors.initials: G
authors.lastname: Jagatheesan
authors.forename: Chehade N
authors.initials: CN
authors.lastname: Karam
authors.forename: Marco L
authors.initials: ML
authors.lastname: Alves
authors.forename: Ilona
authors.initials: I
authors.lastname: Bodi
authors.forename: Arnold
authors.initials: A
authors.lastname: Schwartz
authors.forename: Christian F
authors.initials: CF
authors.lastname: Bulcao
authors.forename: Karen M
authors.initials: KM
authors.lastname: D'Souza
authors.forename: Shahab A
authors.initials: SA
authors.lastname: Akhter
authors.forename: Greg P
authors.initials: GP
authors.lastname: Boivin
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Dube
authors.forename: Natalia
authors.initials: N
authors.lastname: Petrashevskaya
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Herr
authors.forename: Roger
authors.initials: R
authors.lastname: Hullin
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
authors.forename: Beata M
authors.initials: BM
authors.lastname: Wolska
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.forename: David F
authors.initials: DF
authors.lastname: Wieczorek
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000328:Adult; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000503:physiopathology*; D019281:Dimerization; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007536:Isomerism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D009210:Myofibrils / Q000378:metabolism; D020033:Protein Isoforms; D013696:Temperature; D014335:Tropomyosin / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D000199:Actins; D020033:Protein Isoforms; C490775:TPM1 protein, human; D014335:Tropomyosin; D002118:Calcium