Abstract
Aim: Dysfunction of the cardiac ryanodine receptor (RyR2) is an almost ubiquitous finding in animal models of heart failure (HF) and results in abnormal Ca2+ 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 Ca2+ release in rats with post-myocardial infarction HF.Materials and Methods: 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 VO2max test. We repeated echocardiography after 5 weeks of ET and harvested left ventricular cardiomyocytes for analysis of RyR2-dependent systolic and spontaneous Ca2+ release. Phosphoproteins were analyzed by Western blotting, and beta-adrenoceptor density was quantified by radioligand binding.Results: ET increased VO2max in HF-ET rats to 127% of HF-SED (P < 0.05). This coincided with attenuated spontaneous SR Ca2+ release in left ventricular cardiomyocytes from HF-ET but also reduced Ca2+ transient amplitude and slowed Ca2+ reuptake during adrenoceptor activation. However, ventricular diameter and fractional shortening were unaffected by ET. Analysis of Ca2+ homeostasis and major proteins involved in the regulation of SR Ca2+ release and reuptake could not explain the attenuated spontaneous SR Ca2+ release or reduced Ca2+ transient amplitude. Importantly, measurements of beta-adrenoceptors showed a normalization of beta1-adrenoceptor density and beta1:beta2-adrenoceptor ratio in HF-ET.Conclusion: ET increased aerobic capacity in post-myocardial infarction HF rats and stabilized RyR2-dependent Ca2+ release. Our data show that these effects of ET can be gained without major alterations in SR Ca2+ regulatory proteins and indicate that future studies should include upstream parts of the sympathetic signaling pathway.
Highlights
Current guidelines recommend exercise training (ET) as part of rehabilitation programs after myocardial infarction (MI) and for patients with heart failure (HF) [1, 2]
All rats were examined by echocardiography before randomization to ET or standard sedentary conditions (SED) (Figure 1A)
We focused on RyR2 and the FIGURE 1 | long axis are shown for sham-SED (C), sham-ET, HF-SED, and HF-ET rats
Summary
Current guidelines recommend exercise training (ET) as part of rehabilitation programs after myocardial infarction (MI) and for patients with heart failure (HF) [1, 2]. An almost ubiquitous finding in animal models of post-MI HF is a dysfunction of the cardiac ryanodine receptor (RyR2), i.e., the Ca2+ release channel of the sarcoplasmic reticulum (SR) [11, 12]. This channel is essential in normal cellular Ca2+ handling and excitation–contraction coupling [13]. Inhibition of SR Ca2+ leak has been found to prevent arrhythmias in animal models of HF, as well as arrhythmogenic events in cardiac tissue taken from patients with HF, and is a potential future therapeutic strategy [15, 16]. There is a scarcity of data that support such an effect of ET in post-MI HF, and there is a need for rigorous experimental data from clinically relevant models
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