Late-stage alterations in myofibrillar contractile function in a transgenic mouse model of dilated cardiomyopathy (Tgαq*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 G alpha q protein (Tg alpha q*44). The isometric force, its Ca2+ sensitivity (pCa(50)) and the turnover rate of the actin-myosin cycle (k(tu)) were determined at sarcomere lengths (SLs) of 1.9 mu m and 2.3 mu m before (at 4 and 10 months of age) and after hemodynamic decompensation (at 14 and 18 months of age) in Tg alpha q*44 cardiomyocytes and in age-matched control cardiomyocytes. The SL-dependence of pCa(50) was not different in Tg alpha q*44 and control hearts. In contrast, a significant increase in pCa(50) was observed in the Tg alpha q*44 cardiomyocytes (Delta pCa(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 Tg alpha q*44 hearts. Finally, the maximal Ca2+-activated force (F-o) and k(tr) were lower and the passive force (F-passive) was higher at 18 months in the Tg alpha q*44 cardiomyocytes compared to the control. These mechanical alterations were paralleled by a robust increase in beta-myosin heavy chain expression in the Tg alpha q*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 Tg alpha q*44 hearts. (C) 2008 Elsevier Inc. All rights reserved.