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Changes in cAMP signaling are associated with age-related downregulation of spontaneously beating atrial tissue energetic indices
GeroScience ( IF 5.3 ) Pub Date : 2022-07-05 , DOI: 10.1007/s11357-022-00609-0
Noa Kirschner Peretz 1 , Sofia Segal 1 , Rotem Shapira 1 , Ori Shemla 1 , Yevgeniya Lukyanenko 2 , Inbar Brosh 1 , Edward G Lakatta 3 , Kenta Tsutsui 3, 4 , Yael Yaniv 1
Affiliation  

The prevalence of atria-related diseases increases exponentially with age and is associated with ATP supply-to-demand imbalances. Because evidence suggests that cAMP regulates ATP supply-to-demand, we explored aged-associated alterations in atrial ATP supply-to-demand balance and its correlation with cAMP levels. Right atrial tissues driven by spontaneous sinoatrial node impulses were isolated from aged (22–26 months) and adult (3–4 months) C57/BL6 mice. ATP demand increased by addition of isoproterenol or 3-Isobutyl-1-methylxanthine (IBMX) and decreased by application of carbachol. Each drug was administrated at the dose that led to a maximal change in beating rate (Xmax) and to 50% of that maximal change in adult tissue (X50). cAMP, NADH, NAD + NADH, and ATP levels were measured in the same tissue. The tight correlation between cAMP levels and the beating rate (i.e., the ATP demand) demonstrated in adult atria was altered in aged atria. cAMP levels were lower in aged compared to adult atrial tissue exposed to X50 of ISO or IBMX, but this difference narrowed at Xmax. Neither ATP nor NADH levels correlated with ATP demand in either adult or aged atria. Baseline NADH levels were lower in aged as compared to adult atria, but were restored by drug perturbations that increased cAMP levels. Reduction in Ca2+-activated adenylyl cyclase-induced decreased cAMP and prolongation of the spontaneous beat interval of adult atrial tissue to their baseline levels in aged tissue, brought energetics indices to baseline levels in aged tissue. Thus, cAMP regulates right atrial ATP supply-to-demand matching and can restore age-associated ATP supply-to-demand imbalance.



中文翻译:

cAMP 信号的变化与年龄相关的自发搏动心房组织能量指数下调有关

心房相关疾病的患病率随着年龄的增长呈指数增长,并且与 ATP 供需失衡有关。因为有证据表明 cAMP 调节 ATP 供需,我们探讨了与年龄相关的心房 ATP 供需平衡变化及其与 cAMP 水平的相关性。从老年(22-26 个月)和成年(3-4 个月)C57/BL6 小鼠中分离出由自发窦房结冲动驱动的右心房组织。ATP 需求因添加异丙肾上腺素或 3-异丁基-1-甲基黄嘌呤 (IBMX) 而增加,并因应用卡巴胆碱而减少。每种药物的给药剂量可导致搏动率的最大变化 (X max ) 和成人组织最大变化的 50% (X 50). 在同一组织中测量 cAMP、NADH、NAD + NADH 和 ATP 水平。在成人心房中显示的 cAMP 水平与跳动率(即 ATP 需求)之间的紧密相关性在老年心房中发生了改变。与暴露于 X 50 ISO 或 IBMX 的成人心房组织相比,老年人的 cAMP 水平较低,但这种差异在 X max时缩小。ATP 和 NADH 水平都与成人或老年心房的 ATP 需求无关。与成人心房相比,老年人的基线 NADH 水平较低,但通过增加 cAMP 水平的药物扰动得以恢复。Ca 2+减少-激活的腺苷酸环化酶诱导的 cAMP 减少和成人心房组织的自发搏动间隔延长至老年组织的基线水平,使老年组织的能量学指数达到基线水平。因此,cAMP 调节右心房 ATP 供需匹配,可以恢复与年龄相关的 ATP 供需失衡。

更新日期:2022-07-06
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