Post-Myocardial Infarction Exercise Training Reverses Cardiac Excitation-Contraction Coupling Abnormalities by Activating Cytoplasmic CaMKII

Abstract

Post-myocardial infarction (MI) heart failure (HF) leads to abnormal excitation-contraction-coupling (ECC) causing cardiac dysfunctions attributable to hyper-activation of CaMKII. In contrast, exercise improves ECC in post-MI HF, but whether this is through CaMKII remains unknown. Our purpose was to test whether exercise reverses ECC dysfunction in post-MI HF through modulation of CaMKII. Permanent coronary artery ligation leading to HF was induced in Wistar rats. Four weeks after, regular treadmill running started (MI-TRN, n=14). Sham-operated (SHAM, n=12) and sedentary MI-HF (MI-SED, n=16) served as controls. MI-HF reduced exercise capacity 16% (p<0.01); exercise normalised this. Contractile function of twitch-stimulated cardiomyocytes was assessed using edge-detection and Fura-2 fluorescence microscopy with and without the CaMK inhibitor AIP (5uM). MI reduced contraction 40% (p<0.01) and increased contraction-relaxation times. This was explained by reduced Ca2+ transient amplitude and increased Ca2+ rise-decay times. Exercise corrected contraction and contraction-relaxation times, and improved Ca2+ handling. AIP abolished the exercise-induced improvement in contraction and Ca2+ transient amplitude (both p<0.01) and impaired relaxation and Ca2+ transient decay times (p<0.01) more in MI-TRN than MI-SED. Spontaneous Ca2+ waves and sparks were linescan confocal imaged in Fluo-3-loaded cardiomyocytes at normal (1.8mM) and high (5mM) extracellular Ca2+. MI increased wave frequency 65% and amplitude 21% (p<0.01); this was more pronounced at high Ca2+ and reversed by exercise. MI and AIP had no effect on sparks but they were elevated by exercise (p<0.01). AIP had no effect on Ca2+ wave frequency in MI-SED but increased frequency and amplitude in MI-TRN (p<0.05). In conclusion, CaMKII modulated exercise-induced improvements in cardiomyocyte function following MI-HF. In particular, exercise improved sarcoplasmic reticulum (SR) Ca2+-uptake and SR-loading by activating CaMKII, whereas Ca2+ release parameters were less affected. This suggests that exercise activated cytoplasmic, but not dyadic CaMKII.