CaMKII-dependent myofilament Ca2+ desensitization contributes to the frequency-dependent acceleration of relaxation

Abstract

BackgroundPrevious studies suggest that CaMKII activity is required for frequency-dependent acceleration of relaxation (FDAR) in ventricular myocytes. We propose that the underlying mechanism involves CaMKII-dependent regulation of myofilament Ca2+ sensitivity. Methods and resultsCardiac function was measured in mice using murine echo machine. [Ca2+]i and sarcomere length were measured by IonOptix Ca2+ image system. Increasing pacing rate from 0.5 to 4Hz in left ventricular myocytes induced frequency-dependent myofilament Ca2+ desensitization (FDMCD) and FDAR. Acute inhibition of PKA or PKC had no effect, whereas CaMKII inhibition abolished both FDMCD and FDAR. Co-immunoprecipitation of CaMKII and troponin I (TnI) has been detected and CaMKII inhibition significantly reduced serine residue phosphorylation of TnI. Finally, chronic inhibition of CaMKII in vivo reduced TnI phosphorylation and abolished both FDAR and FDMCD, leading to impaired diastolic function. ConclusionsOur results suggest that CaMKII-dependent TnI phosphorylation is involved in FDMCD and the consequent FDAR and that CaMKII inhibition removes this mechanism and thus induces diastolic dysfunction.