Cardiac-specific mutation of Clock alters the quantitative measurements of physical activities without changing behavioral circadian rhythms.
Cardiac-specific mutation of Clock alters the quantitative measurements of physical activities without changing behavioral circadian rhythms.
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DOI：
10.1177/0748730411414170
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发表时间：
2011-10
影响因子：
3.5
通讯作者：
Ko GY
中科院分区：
文献类型：
--
作者：
Ko ML;Shi L;Tsai JY;Young ME;Neuendorff N;Earnest DJ;Ko GY
尽管已知心血管系统中存在外周昼夜节律振荡器，但心血管系统的日常节律主要归因于中央振荡器视交叉上核（SCN）控制下的自主或激素输入。为了检查外周振荡器在心血管系统中的作用，我们使用了转基因小鼠，其中心肌细胞中的时钟基因被特异性破坏。在这种心肌细胞特异性 CLOCK 突变体 (CCM) 小鼠模型中，来自 SCN 的昼夜节律输入保持完整。 CCM 和野生型（WT）同窝动物在轮跑行为中都表现出昼夜节律。然而，在 5 周内，与 WT 相比，CCM 小鼠的总体跑轮活动明显较低，这表明 CCM 小鼠要么具有较低的基线身体活动，要么具有较低的身体适应能力，因为每天的跑轮与常规锻炼一样，会在一段时间内诱导身体适应。进一步的生化分析表明，WT心脏中发现的几种激酶的磷酸化状态和L型电压门控钙通道（L-VGCC）α1D亚基的蛋白质表达的昼夜振荡在CCM心脏中被消除，这表明在哺乳动物心脏中，这些激酶和L-VGCC的活性的日振荡是下游的 心脏核心振荡器的元素。然而，p38 MAPK 的磷酸化在 WT 和 CCM 心脏中均表现出强烈的昼夜节律，表明心脏 p38 可能通过神经激素信号受到中央时钟的影响，或者成为心肌细胞昼夜节律输入途径的一部分。综上所述，这些结果表明心脏核心振荡器对调节昼夜节律和心脏功能具有影响。
Even though peripheral circadian oscillators in the cardiovascular system are known to exist, the daily rhythms of the cardiovascular system are mainly attributed to autonomic or hormonal inputs under the control of the central oscillator, the suprachiasmatic nucleus (SCN). In order to examine the role of peripheral oscillators in the cardiovascular system, we used a transgenic mouse where the Clock gene is specifically disrupted in cardiomyocytes. In this cardiomyocyte-specific CLOCK mutant (CCM) mouse model, the circadian input from the SCN remains intact. Both CCM and wild-type (WT) littermates displayed circadian rhythms in wheel-running behavior. However, the overall wheel-running activities were significantly lower in CCM mice compared to WT over the course of 5 weeks, indicating that CCM mice either have lower baseline physical activities or they have lower physical adaptation abilities because daily wheel running, like routine exercise, induces physical adaptation over a period of time. Upon further biochemical analysis, it was revealed that the diurnal oscillations of phosphorylation states of several kinases and protein expression of the L-type voltage-gated calcium channel (L-VGCC) α1D subunit found in WT hearts were abolished in CCM hearts, indicating that in mammalian hearts, the daily oscillations of the activities of these kinases and L-VGCCs were downstream elements of the cardiac core oscillators. However, the phosphorylation of p38 MAPK exhibited robust diurnal rhythms in both WT and CCM hearts, indicating that cardiac p38 could be under the influence of the central clock through neurohormonal signals or be part of the circadian input pathway in cardiomyocytes. Taken together, these results indicate that the cardiac core oscillators have an impact in regulating circadian rhythmicities and cardiac function.
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影响因子：
5.5
作者：
Gaborit, Nathalie;Le Bouter, Sabrina;Demolombe, Sophie
通讯作者：
Demolombe, Sophie
影响因子：
2.8
作者：
Ko ML;Shi L;Grushin K;Nigussie F;Ko GY
通讯作者：
Ko GY
影响因子：
20.1
作者：
Durgan DJ;Pulinilkunnil T;Villegas-Montoya C;Garvey ME;Frangogiannis NG;Michael LH;Chow CW;Dyck JR;Young ME
通讯作者：
Young ME
影响因子：
4.7
作者：
Ko, Michael L.;Liu, Yilin;Ko, Gladys Y. -P.
通讯作者：
Ko, Gladys Y. -P.
DOI：
10.1073/pnas.0811410106
发表时间：
2008-12-30
影响因子：
11.1
作者：
Hirota, Tsuyoshi;Lewis, Warren G.;Kay, Steve A.
通讯作者：
Kay, Steve A.