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首页> 外文期刊>Molecular and Cellular Biology >Altered Extracellular Signal-Regulated Kinase Signaling and Glycogen Metabolism in Skeletal Muscle from p90 Ribosomal S6 Kinase 2 Knockout Mice
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Altered Extracellular Signal-Regulated Kinase Signaling and Glycogen Metabolism in Skeletal Muscle from p90 Ribosomal S6 Kinase 2 Knockout Mice

机译：从p90核糖体S6激酶2基因敲除小鼠骨骼肌中的细胞外信号调节激酶信号转导和糖原代谢。

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The p90 ribosomal S6 kinase (RSK), a cytosolic substrate for the extracellular signal-regulated kinase (ERK), is involved in transcriptional regulation, and one isoform (RSK2) has been implicated in the activation of glycogen synthase by insulin. To determine RSK2 function in vivo, mice lacking a functional rsk2 gene were generated and studied in response to insulin and exercise, two potent stimulators of the ERK cascade in skeletal muscle. RSK2 knockout (KO) mice weigh 10% less and are 14% shorter than wild-type (WT) mice. They also have impaired learning and coordination. Hindlimb skeletal muscles were obtained from mice 10, 15, or 30 min after insulin injection or immediately after strenuous treadmill exercise for 60 min. While insulin and exercise significantly increased ERK phosphorylation in skeletal muscle from both WT and KO mice, the increases were twofold greater in the KO animals. This occurred despite 27% lower ERK2 protein expression in skeletal muscle of KO mice. KO mice had 18% less muscle glycogen in the fasted basal state, and insulin increased glycogen synthase activity more in KO than WT mice. The enhanced insulin-stimulated increases in ERK and glycogen synthase activities in KO mice were not associated with higher insulin receptor or with IRS1 tyrosine phosphorylation or with IRS1 binding to phosphatidylinositol 3-kinase. However, insulin-stimulated serine phosphorylation of Akt was significantly higher in the KO animals. c-fos mRNA was increased similarly in muscle from WT and KO mice in response to insulin (2.5-fold) and exercise (15-fold). In conclusion, RSK2 likely plays a major role in feedback inhibition of the ERK pathway in skeletal muscle. Furthermore, RSK2 is not required for activation of muscle glycogen synthase by insulin but may indirectly modulate muscle glycogen synthase activity and/or glycogen content by other mechanisms, possibly through regulation of Akt. RSK2 knockout mice may be a good animal model for the study of Coffin-Lowry syndrome.
机译：p90核糖体S6激酶（RSK）是细胞外信号调节激酶（ERK）的胞质底物，参与转录调节，一种同工型（RSK2）与胰岛素激活糖原合酶有关。为了确定体内RSK2的功能，产生了缺乏功能性 rsk2 基因的小鼠，并根据胰岛素和运动对骨骼肌中ERK的两种有效刺激物进行了级联研究。与野生型（WT）小鼠相比，RSK2基因敲除（KO）小鼠的体重减轻了10％，短了14％。他们的学习和协调能力也受到损害。胰岛素注射后10、15或30分钟或剧烈跑步运动60分钟后立即从小鼠获得后肢骨骼肌。尽管胰岛素和运动显着增加了WT和KO小鼠骨骼肌中ERK磷酸化的水平，但在KO动物中，其增加了两倍。尽管KO小鼠骨骼肌中ERK2蛋白表达降低了27％，但仍发生了这种情况。在禁食的基础状态下，KO小鼠的肌肉糖原减少了18％，并且胰岛素比WT小鼠在KO中的糖原合酶活性更高。 KO小鼠中胰岛素刺激的ERK和糖原合酶活性的增强与更高的胰岛素受体，IRS1酪氨酸磷酸化或IRS1与磷脂酰肌醇3-激酶的结合无关。然而，在KO动物中，胰岛素刺激的Akt的丝氨酸磷酸化明显更高。 WT和KO小鼠肌肉中的c- fos mRNA在胰岛素（2.5倍）和运动（15倍）的响应下也相似地增加。总之，RSK2可能在骨骼肌ERK途径的反馈抑制中起主要作用。此外，RSK2不是胰岛素激活肌肉糖原合酶所必需的，但可能通过其他机制（可能通过调节Akt）间接调节肌肉糖原合酶活性和/或糖原含量。 RSK2基因敲除小鼠可能是研究棺材-Lowry综合征的好动物模型。

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