Genetic disruption of the cardiomyocyte circadian clock differentially influences insulin-mediated processes in the heart.
Genetic disruption of the cardiomyocyte circadian clock differentially influences insulin-mediated processes in the heart.
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DOI：
10.1016/j.yjmcc.2017.07.005
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发表时间：
2017-09
影响因子：
5
通讯作者：
Young ME
中科院分区：
文献类型：
--
作者：
McGinnis GR;Tang Y;Brewer RA;Brahma MK;Stanley HL;Shanmugam G;Rajasekaran NS;Rowe GC;Frank SJ;Wende AR;Abel ED;Taegtmeyer H;Litovsky S;Darley-Usmar V;Zhang J;Chatham JC;Young ME
心血管生理学表现出一天中的时间依赖性振荡，这是由外在的（例如，环境/行为）和内在（例如，生物钟）因素。昼夜节律的破坏对多个心脏代谢参数产生负面影响。最近的研究表明，心肌细胞生物钟直接调节心脏对代谢刺激的反应性（例如，脂肪酸）和应激（例如，缺血/再灌注）。本研究的目的是确定心肌细胞生物钟的遗传破坏是否会影响心脏中的胰岛素调节途径。心肌细胞特异性Bmal 1敲除（CBK）和心肌细胞特异性Clock突变（CCM）小鼠中生物钟的遗传破坏改变了心脏中多种胰岛素信号传导组分（包括p85α和Akt）的表达（基因和蛋白质）。基线和胰岛素介导的Akt激活在CBK和CCM心脏中均增强（相对于同窝对照）。然而，胰岛素介导的葡萄糖利用（氧化和非氧化）和AS 160磷酸化在CBK心脏中减弱，可能继发于抑制剂-1减少。与CBK心脏中Akt活化增加一致，mTOR信号传导持续增加，这与自噬减弱、蛋白质合成速率增加和肥大相关。重要的是，mTOR（雷帕霉素; 10天）的药理学抑制使CBK小鼠中的心脏大小正常化。这些数据表明，心肌细胞昼夜节律钟的破坏差异影响胰岛素调节的过程，并提供了新的见解昼夜节律破坏后的潜在病理介质。
Cardiovascular physiology exhibits time-of-day-dependent oscillations, which are mediated by both extrinsic (e.g., environment/behavior) and intrinsic (e.g., circadian clock) factors. Disruption of circadian rhythms negatively affects multiple cardiometabolic parameters. Recent studies suggest that the cardiomyocyte circadian clock directly modulates responsiveness of the heart to metabolic stimuli (e.g., fatty acids) and stresses (e.g., ischemia/reperfusion). The aim of this study was to determine whether genetic disruption of the cardiomyocyte circadian clock impacts insulin-regulated pathways in the heart. Genetic disruption of the circadian clock in cardiomyocyte-specific Bmal1 knockout (CBK) and cardiomyocyte-specific Clock mutant (CCM) mice altered expression (gene and protein) of multiple insulin signaling components in the heart, including p85α and Akt. Both baseline and insulin-mediated Akt activation was augmented in CBK and CCM hearts (relative to littermate controls). However, insulin-mediated glucose utilization (both oxidative and non-oxidative) and AS160 phosphorylation were attenuated in CBK hearts, potentially secondary to decreased Inhibitor-1. Consistent with increased Akt activation in CBK hearts, mTOR signaling was persistently increased, which was associated with attenuation of autophagy, augmented rates of protein synthesis, and hypertrophy. Importantly, pharmacological inhibition of mTOR (rapamycin; 10 days) normalized cardiac size in CBK mice. These data suggest that disruption of cardiomyocyte circadian clock differentially influences insulin-regulated processes, and provide new insights into potential pathologic mediators following circadian disruption.
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影响因子：
8.1
作者：
Dyar KA;Ciciliot S;Wright LE;Biensø RS;Tagliazucchi GM;Patel VR;Forcato M;Paz MI;Gudiksen A;Solagna F;Albiero M;Moretti I;Eckel-Mahan KL;Baldi P;Sassone-Corsi P;Rizzuto R;Bicciato S;Pilegaard H;Blaauw B;Schiaffino S
通讯作者：
Schiaffino S
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
DOI：
10.1152/ajpheart.00075.2014
发表时间：
2014-04-01
影响因子：
4.8
作者：
Collins, Helen E.;He, Lan;Chatham, John C.
通讯作者：
Chatham, John C.
影响因子：
7
作者：
Gibson, UEM;Heid, CA;Williams, PM
通讯作者：
Williams, PM
影响因子：
7
作者：
Heid, CA;Stevens, J;Williams, PM
通讯作者：
Williams, PM