Insulin-like growth factor I-mediated skeletal muscle hypertrophy is characterized by increased mTOR-p70S6K signaling without increased Akt phosphorylation
Insulin-like growth factor I-mediated skeletal muscle hypertrophy is characterized by increased mTOR-p70S6K signaling without increased Akt phosphorylation
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DOI：
10.2310/6650.2005.00309
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发表时间：
2005-04-01
影响因子：
2.6
通讯作者：
Delafontaine, P
中科院分区：
文献类型：
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作者：
Song, YH;Godard, M;Delafontaine, P
背景：胰岛素样生长因子I（IGF-I）是一种已知可诱导骨骼肌肥大的合成代谢激素。方法：采用Kinetworks蛋白质组学方法，对过表达IGF-I肌球蛋白轻链/肌肉特异性IGF-I的转基因小鼠腓肠肌中46种蛋白质的磷酸化进行研究（MLC/mlgf-I）和野生型同窝仔。在MLC/mlgf-I小鼠的肥大肌肉中，我们观察到磷酸肌醇依赖性蛋白激酶1的磷酸化增加，（PDK 1;增加53%）、雷帕霉素的哺乳动物靶标（mTOR;增加112%）和p70 S6激酶（p70 S6 K）（增加254%），但Akt磷酸化没有显著变化（减少4%）。此外，我们发现MAP激酶激酶1和2（MEK 1/2）的磷酸化减少，（降低60%）和丝裂原活化蛋白激酶激酶3和6（MKK 3/6）（减少50%），这表明IGF-I的肥大和促有丝分裂作用是通过骨骼肌中不同的信号通路介导的，激酶途径可能是IGF-I诱导的肥大效应所必需的。单纤维分析显示，在转基因mice.Conclusion中，IGF-I在小鼠骨骼肌中的持续过表达导致肥大，这可能是通过mTOF/p70 S6 K通路介导的，可能是通过Akt非依赖性信号通路。
Background: Insulin-like growth factor I (IGF-I) is an anabolic hormone that is known to induce skeletal muscle hypertrophy. However, the signaling pathways mediating IGF-I's hypertrophic effect in vivo are unknown.Method: The phosphorylation of 46 proteins was investigated by Kinetworks proteomic analysis in the gastrocnemius muscle of transgenic mice overexpressing IGF-I myosin light chain/muscle specific IGF-I (MLC/mlgf-I) and wild-type littermates.Results: In the hypertrophic muscle of MLC/mlgf-I mice, we observed increased phosphorylation of phosphoinositidedependent protein kinase 1 (PDK1; 53% increase), the mammalian target of rapamycin (mTOR; 112% increase), and p70 S6 kinase (p70S6K) (254% increase) but no significant change in Akt phosphorylation (4% decrease). Furthermore, we found reduced phosphorylation of MAP kinase kinase 1 and 2 (MEK1/2) (60% decrease) and of mitogen-activated protein kinase kinases 3 and 6 (MKK3/6) (50% decrease) in muscle from transgenic mice, suggesting that the hypertrophic and mitogenic effects of IGF-I are mediated via distinct signaling pathways in skeletal muscle and that inhibition of the mitogen-activated protein (MAP) kinase pathway may be required for the IGF-I-induced hypertrophic effect. Single-fiber analysis revealed a trend toward a higher percentage of the fast twitch fibers (IIb and IIx) in the transgenic mice.Conclusion: Persistent overexpression of IGF-I in mice skeletal muscle results in hypertrophy, which is likely mediated via the mTOF/p70S6K pathway, potentially via an Akt-independent signaling pathway.