Abstract 3848: Enhanced Myofilament Responsiveness Upon β-Adrenergic Stimulation in Post-infarct Remodeled Myocardium Mediated by Increased Ca2+-Dependent Calmodulin Kinase II Activity
The left ventricular (LV) responsiveness to exercise-induced increases in noradrenaline is blunted in pigs with a recent myocardial infarction (MI), consistent with defects in β-adrenergic receptor (β-AR) signaling. Here we studied myofilament function and protein composition in remote LV biopsies taken at baseline and during dobutamine stimulation 3 weeks after MI versus sham. At baseline single permeabilized pig ventricular cardiomyocytes demonstrated reduced maximal force (Fmax) and higher Ca2+-sensitivity in MI compared to sham. Fmax did not change during dobutamine in sham, but markedly increased in MI and dobutamine induced a larger decrease in Ca2+-sensitivity (ΔEC50; Figure⇓) in MI than sham. Baseline phosphorylation (ProQ Diamond phosphostaining) of β-AR target proteins myosin binding protein C (cMyBP-C) and troponin I (cTnI) was not altered in MI, although the dobutamine-induced cTnI phosphorylation was lower in MI than in sham (Figure⇓). Similarly, dobutamine caused lower phosphorylation of cTnI at protein kinase A (PKA)-sites (Ser23/24) in MI compared to sham. Noteworthy, dobutamine-induced phosphorylation of cMyBP-C at Ser282 was preserved in MI, and coincided with increased autophosphorylation (at Thr287) of the cytosolic Ca2+-dependent calmodulin kinase II (CaMKII-δC)(Figure⇓). In pigs with MI myofilament responsiveness to dobutamine is significantly enhanced despite the lower increase in PKA-phosphorylation of cTnI. The stronger myofilament responsiveness in MI may depend on the preserved cMyBP-C phosphorylation, possibly resulting from increased CaMKII-δC activity, and may help to maintain proper diastolic performance during exercise.