Danielsen Tore Kristian, Sadredini Mani, Manotheepan Ravinea, Aronsen Jan Magnus, Frisk Michael, Hansen Marie Haugsten, Andressen Kjetil Wessel, Hougen Karina, Levy Finn Olav, Louch William E, Sejersted Ole Mathias, Sjaastad Ivar, Stokke Mathis Korseberg
Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, Oslo, Norway.
Kristian Gerhard (KG) Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway.
Front Cardiovasc Med. 2021 Jan 25;7:623922. doi: 10.3389/fcvm.2020.623922. eCollection 2020.
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.
心脏兰尼碱受体（RyR2）功能障碍在心力衰竭（HF）动物模型中几乎普遍存在，可导致心肌细胞钙释放异常，进而导致收缩功能受损和心律失常。我们测试了按照当前指南推荐的运动训练（ET）是否有可能稳定心肌梗死后HF大鼠中依赖RyR2的钙释放。我们对雄性Wistar大鼠进行左冠状动脉结扎或假手术。1周后，通过超声心动图对动物进行表征，并随机分为跑步机上的高强度间歇ET组或久坐行为（SED）组。根据每周的VO测试调整跑步速度。ET 5周后重复超声心动图检查，并收获左心室心肌细胞以分析依赖RyR2的收缩期和自发性钙释放。通过蛋白质免疫印迹分析磷酸化蛋白，并通过放射性配体结合定量β-肾上腺素能受体密度。ET使HF-ET大鼠的VO增加至HF-SED大鼠的127%（P<0.05）。这与HF-ET大鼠左心室心肌细胞中自发性肌浆网（SR）钙释放减弱同时发生，但也降低了钙瞬变幅度，并减缓了肾上腺素能受体激活期间的钙再摄取。然而，心室直径和缩短分数不受ET影响。对钙稳态以及参与SR钙释放和再摄取调节的主要蛋白质的分析无法解释自发性SR钙释放减弱或钙瞬变幅度降低的原因。重要的是，β-肾上腺素能受体测量显示HF-ET组中β-肾上腺素能受体密度和β：β-肾上腺素能受体比率正常化。ET增加了心肌梗死后HF大鼠的有氧能力，并稳定了依赖RyR2的钙释放。我们的数据表明，ET的这些作用可以在SR钙调节蛋白无重大改变的情况下获得，并表明未来的研究应包括交感信号通路的上游部分。
