Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform.
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.
Rajan
Sudarsan
S
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati Medical Center, Cincinnati, OH 45267-0524, USA.
Jagatheesan
Ganapathy
G
Karam
Chehade N
CN
Alves
Marco L
ML
Bodi
Ilona
I
Schwartz
Arnold
A
Bulcao
Christian F
CF
D'Souza
Karen M
KM
Akhter
Shahab A
SA
Boivin
Greg P
GP
Dube
Dipak K
DK
Petrashevskaya
Natalia
N
Herr
Andrew B
AB
Hullin
Roger
R
Liggett
Stephen B
SB
Wolska
Beata M
BM
Solaro
R John
RJ
Wieczorek
David F
DF
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
D000199:Actins; D020033:Protein Isoforms; C490775:TPM1 protein, human; D014335:Tropomyosin; D002118:Calcium