Myofilament dysfunction is a common point of convergence for many forms of
heart failure. Recently, we showed that cardiac overexpression of
PKC epsilon initially depresses myofilament activity and then leads to a progression of changes characteristic of human
heart failure. Here, we examined the effects of
PKC epsilon on contractile reserve, Starling mechanism, and myofilament activation in this model of end-stage
dilated cardiomyopathy. Pressure-volume loop analysis and echocardiography showed that the
PKC epsilon mice have markedly compromised systolic function and increased end-diastolic volumes.
Dobutamine challenge resulted in a small increase in contractility in
PKC epsilon mice but failed to enhance cardiac output. The
PKC epsilon mice showed a normal length-dependent tension development in skinned cardiac muscle preparations, although Frank-Starling mechanism appeared to be compromised in the intact animal. Simultaneous measurement of tension and
ATPase demonstrated that the maximum tension and
ATPase were markedly lower in the
PKC epsilon mice at any length or Ca2+ concentration. However, the tension cost was also lower indicating less energy expenditure. We conclude 1) that prolonged overexpression of
PKC epsilon ultimately leads to a
dilated cardiomyopathy marked by exhausted contractile reserve, 2) that
PKC epsilon does not compromise the Frank-Starling mechanism at the myofilament level, and 3) that the Starling curve excursion is limited by the inotropic state of the heart. These results reflect the significance of the primary myofilament contractilopathy induced by phosphorylation and imply a role for
PKC epsilon-mediated phosphorylation in myofilament physiology and the pathophysiology of decompensated
cardiac failure.