Exercise Training Stabilizes RyR2-Dependent Ca Release in Post-infarction Heart Failure.

Dysfunction of the cardiac ryanodine receptor (RyR2) is an almost ubiquitous finding in animal models of heart failure (HF) and results in abnormal Ca release in cardiomyocytes that contributes to contractile impairment and arrhythmias. We tested whether exercise training (ET), as recommended by current guidelines, had the potential to stabilize RyR2-dependent Ca release in rats with post-myocardial infarction HF. We subjected male Wistar rats to left coronary artery ligation or sham operations. After 1 week, animals were characterized by echocardiography and randomized to high-intensity interval ET on treadmills or to sedentary behavior (SED). Running speed was adjusted based on a weekly VO test. We repeated echocardiography after 5 weeks of ET and harvested left ventricular cardiomyocytes for analysis of RyR2-dependent systolic and spontaneous Ca release. Phosphoproteins were analyzed by Western blotting, and beta-adrenoceptor density was quantified by radioligand binding. ET increased VO in HF-ET rats to 127% of HF-SED ( < 0.05). This coincided with attenuated spontaneous SR Ca release in left ventricular cardiomyocytes from HF-ET but also reduced Ca transient amplitude and slowed Ca reuptake during adrenoceptor activation. However, ventricular diameter and fractional shortening were unaffected by ET. Analysis of Ca homeostasis and major proteins involved in the regulation of SR Ca release and reuptake could not explain the attenuated spontaneous SR Ca release or reduced Ca transient amplitude. Importantly, measurements of beta-adrenoceptors showed a normalization of beta-adrenoceptor density and beta:beta-adrenoceptor ratio in HF-ET. ET increased aerobic capacity in post-myocardial infarction HF rats and stabilized RyR2-dependent Ca release. Our data show that these effects of ET can be gained without major alterations in SR Ca regulatory proteins and indicate that future studies should include upstream parts of the sympathetic signaling pathway.