MLP and CARP are linked to chronic PKCα signalling in dilated cardiomyopathy

MLP (muscle LIM protein)-deficient mice count among the first mouse models for dilated cardiomyopathy (DCM), yet the exact role of MLP in cardiac signalling processes is still enigmatic. Elevated PKC alpha signalling activity is known to be an important contributor to heart failure. Here we show that MLP directly inhibits the activity of PKC alpha. In end-stage DCM, PKC alpha is concentrated at the intercalated disc of cardiomyocytes, where it is sequestered by the adaptor protein CARP in a multiprotein complex together with PLC beta 1. In mice deficient for both MLP and CARP the chronic PKC alpha signalling chain at the intercalated disc is broken and they remain healthy. Our results suggest that the main role of MLP in heart lies in the direct inhibition of PKC alpha and that chronic uninhibited PKC alpha activity at the intercalated disc in the absence of functional MLP leads to heart failure.