Altered extracellular signal-regulated kinase signaling and glycogen metabolism in skeletal muscle from p90 ribosomal S6 kinase 2 knockout mice
Altered extracellular signal-regulated kinase signaling and glycogen metabolism in skeletal muscle from p90 ribosomal S6 kinase 2 knockout mice
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DOI：
10.1128/mcb.21.1.81-87.2001
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发表时间：
2001-01-01
影响因子：
5.3
通讯作者：
Goodyear, LJ
中科院分区：
文献类型：
--
作者：
Dufresne, SD;Bjorbæk, C;Goodyear, LJ
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，其中一种亚型（RSK 2）与胰岛素激活糖原合成酶有关。为了确定RSK 2在体内的功能，产生了缺乏功能性rsk 2基因的小鼠，并研究了对胰岛素和运动的反应，这两种是骨骼肌中ERK级联的两种有效刺激物。RSK 2敲除（KO）小鼠的体重比野生型（WT）小鼠轻10%，矮14%。他们的学习和协调能力也受损。注射胰岛素后10、15或30分钟或剧烈跑步机运动60分钟后立即从小鼠中获取后肢骨骼肌。虽然胰岛素和运动显着增加了WT和KO小鼠骨骼肌中的ERK磷酸化，但增加幅度是KO小鼠的两倍。动物。尽管KO小鼠骨骼肌中ERK 2蛋白表达降低了27%，但仍发生了这种情况。KO小鼠在禁食基础状态下肌糖原减少18%，KO小鼠中胰岛素增加糖原合成酶活性的程度高于WT小鼠。增强胰岛素刺激增加ERK和糖原合成酶活性在KO小鼠与更高的胰岛素受体或IRS 1酪氨酸磷酸化或IRS 1结合磷脂酰肌醇3-激酶。然而，胰岛素刺激的Akt的丝氨酸磷酸化在KO动物中显著更高，来自WT和KO小鼠的肌肉中的c-fos mRNA响应于胰岛素（2.5倍）和运动（15倍）而类似地增加。总之，RSK 2可能在骨骼肌ERK通路的反馈抑制中起主要作用。此外，RSK 2不是胰岛素激活肌糖原合酶所必需的，但可能通过其他机制（可能通过调节Akt）间接调节肌糖原合酶活性和/或糖原含量。RSK 2基因敲除小鼠可能是研究Coffin-Lowry综合征的良好动物模型。
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.