Late-stage alterations in myofibrillar contractile function in a transgenic mouse model of dilated cardiomyopathy (Tgalphaq*44).
Mechanical and biochemical alterations were investigated in permeabilized cardiomyocytes along with the progression of dilated cardiomyopathy (DCM) in a transgenic mouse line overexpressing the activated Galphaq protein (Tgalphaq*44). The isometric force, its Ca(2+) sensitivity (pCa(50)) and the turnover rate of the actin-myosin cycle (k(tr)) were determined at sarcomere lengths (SLs) of 1.9 mum and 2.3 mum before (at 4 and 10 months of age) and after hemodynamic decompensation (at 14 and 18 months of age) in Tgalphaq*44 cardiomyocytes and in age-matched control cardiomyocytes. The SL-dependence of pCa(50) was not different in Tgalphaq*44 and control hearts. In contrast, a significant increase in pCa(50) was observed in the Tgalphaq*44 cardiomyocytes (DeltapCa(50): 0.10-0.15 vs. the controls) after 10 months of age that could be diminished by exposures to the catalytic subunit of protein kinase A (PKA). Accordingly, a decline in endogenous PKA activity and decreased troponin I phosphorylation were detected after 10 months in the Tgalphaq*44 hearts. Finally, the maximal Ca(2+)-activated force (F(o)) and k(tr) were lower and the passive force (F(passive)) was higher at 18 months in the Tgalphaq*44 cardiomyocytes compared to the control. These mechanical alterations were paralleled by a robust increase in beta-myosin heavy chain expression in the Tgalphaq*44 hearts. In conclusion, our data suggested that an initial decrease of PKA signaling and subsequent changes in myofilament protein expression may contribute to the development of dilated cardiomyopathy in Tgalphaq*44 hearts.
Edes
István Ferenc
IF
Division of Clinical Physiology, Institute of Cardiology University of Debrecen, Medical and Health Science Center, Faculty of Medicine Móricz Zs. krt. 22. H-4032 Debrecen, Hungary.
Tóth
Attila
A
Csányi
Gábor
G
Lomnicka
Magdalena
M
Chłopicki
Stefan
S
Edes
István
I
Papp
Zoltán
Z
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D002417:Cattle; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology; D009210:Myofibrils / Q000235:genetics / Q000502:physiology*
D043802:GTP-Binding Protein alpha Subunits, Gq-G11