Differential interactions of thin filament proteins in two cardiac troponin T mouse models of hypertrophic and dilated cardiomyopathies.
OBJECTIVE
Mutations in a sarcomeric protein can cause hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM), the opposite ends of a spectrum of phenotypic responses of the heart to mutations. We posit the contracting phenotypes could result from differential effects of the mutant proteins on interactions among the sarcomeric proteins. To test the hypothesis, we generated transgenic mice expressing either cardiac troponin T (cTnT)-Q92 or cTnT-W141, known to cause HCM and DCM, respectively, in the heart.


RESULTS
We phenotyped the mice by echocardiography, histology and immunoblotting, and real-time polymerase chain reaction. We detected interactions between the sarcomeric proteins by co-immunoprecipitation and determined Ca2+ sensitivity of myofibrillar protein ATPase activity by Carter assay. The cTnT-W141 mice exhibited dilated hearts and decreased systolic function. In contrast, the cTnT-Q92 mice showed smaller ventricles and enhanced systolic function. Levels of cardiac troponin I, cardiac alpha-actin, alpha-tropomyosin, and cardiac troponin C co-immunoprecipitated with anti-cTnT antibodies were higher in the cTnT-W141 than in the cTnT-Q92 mice, as were levels of alpha-tropomyosin co-immunoprecipitated with an anti-cardiac alpha-actin antibody. In contrast, levels of cardiac troponin I co-immunoprecipitated with an anti-cardiac alpha-actin antibody were higher in the cTnT-Q92 mice. Ca2+ sensitivity of myofibrillar ATPase activity was increased in HCM but decreased in DCM mice compared with non-transgenic mice.


CONCLUSIONS
Differential interactions among the sarcomeric proteins containing cTnT-Q92 or cTnT-W141 are responsible for the contrasting phenotypes of HCM or DCM, respectively.
Lombardi
Raffaella
R
Center for Cardiovascular Genetic Research, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, 6770 Bertner Street, Suite C900A, Houston, TX 77030, USA.
Bell
Achim
A
Senthil
Vinitha
V
Sidhu
Jasvinder
J
Noseda
Michela
M
Roberts
Robert
R
Marian
Ali J
AJ
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D020098:Natriuretic Peptide, C-Type / Q000378:metabolism; D010641:Phenotype; D011498:Protein Precursors / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism; D020107:Troponin T / Q000235:genetics / Q000378:metabolism*; D014463:Ultrasonography
C431578:Nppa protein, mouse; D011498:Protein Precursors; D020107:Troponin T; D020098:Natriuretic Peptide, C-Type; D009320:Atrial Natriuretic Factor; D000251:Adenosine Triphosphatases; D002118:Calcium