Role of the insulin-like growth factor I decline in the induction of atrogin-1/MAFbx during fasting and diabetes
Role of the insulin-like growth factor I decline in the induction of atrogin-1/MAFbx during fasting and diabetes
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DOI：
10.1210/en.2004-0406
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发表时间：
2004-11-01
期刊：
影响因子：
4.8
通讯作者：
Thissen, JP
中科院分区：
文献类型：
--
作者：
Dehoux, M;Van Beneden, R;Thissen, JP
在分解代谢的条件下，肌肉萎缩所需的肌肉特异性泛素连接酶-1/MAFbx增加，而IGF-I浓度减少，IGF-I是一种已知具有抗蛋白分解作用的生长因子。为探讨胰岛素样生长因子-I(IGF-I)水平下降与阿托品-1/MAFbx诱导的关系，我们观察了胰岛素样生长因子-I(IGF-I)替代对禁食51h大鼠和链脲佐菌素(STZ)诱导的糖尿病大鼠阿托金-1/MAFbx基因表达的影响。禁食使阿托金-1/MAFbx增加了5.8倍(P<；0.001)。注射IGF-I后，这种增加减弱到2.5倍(P<；0.05与禁食相比)。患有链脲佐菌素诱导的糖尿病的动物经历了15.1倍的阿托金-1/MAFbx增加(P<；0.001)。通过输注IGF-I使其循环中的IGF-I浓度正常化，将阿托金-1/MAFbx的诱导钝化至6.3倍(P<；0.05与不注射IGF-I的STZ糖尿病相比)。为了进一步阐明IGF-I对阿托金-1/MAFbx的调节，我们研究了一个培养的肌细胞模型。我们观察到IGF-I呈时间和剂量依赖性地降低阿托金-1/MAFbx的mRNA，其有效剂量为生理浓度5 nM IGF-I的50%。IGF-I对阿托金-1/MAFbx基因的降解速率无明显影响，提示IGF-I对阿托金-1/MAFbx基因表达的下调可能是一种转录效应。培养的肌细胞暴露于地塞米松可增加阿托金-1/MAFbx基因的表达，其有效剂量为10 nM，为药物浓度的50%。在地塞米松存在的情况下，生理浓度的IGF-I对阿托金-1/MAFbx的mRNA仍有完全的抑制作用。我们得出结论，IGF-I抑制阿托金-1/MAFbx的表达，推测这种作用可能与IGF-I在肌肉中的抗蛋白分解作用有关。
In catabolic conditions, atrogin-1/MAFbx, a muscle-specific ubiquitin-ligase required for muscle atrophy, is increased, and concentrations of IGF-I, a growth factor known to have antiproteolytic action, are reduced. To define the relationship between the decline in IGF-I and the induction of atrogin-1/MAFbx, we studied the effect of IGF-I replacement on atrogin1/MAFbx mRNA in rats fasted for 51 h and in rats made diabetic with streptozotocin (STZ). Fasting produced a 5.8-fold increase in atrogin-1/MAFbx (P < 0.001). This was attenuated to a 2.5-fold increase by injections of IGF-I (P < 0.05 vs. fasting). Animals with STZ-induced diabetes experienced a 15.1-fold increase in atrogin-1/MAFbx (P < 0.001). Normalization of their circulating IGF-I concentrations by IGF-I infusion blunted the induction of atrogin-1/MAFbx to 6.3-fold ( P < 0.05 vs. STZ diabetes without IGF-I). To further delineate the regulation of atrogin-1/MAFbx by IGF-I, we studied a model of cultured muscle cells. We observed that IGF-I produced a time- and dose-dependent reduction of atrogin-1/MAFbx mRNA, with a 50% effective dose of 5 nM IGF-I, a physiological concentration. The degradation rate of atrogin-1/MAFbx mRNA was not affected by IGF-I, suggesting that the reduction of atrogin-1/MAFbx mRNA by IGF-I is a transcriptional effect. Exposure of muscle cells in culture to dexamethasone increased atrogin-1/MAFbx mRNA with a 50% effective dose of 10 nM, a pharmacological concentration. In the presence of dexamethasone, IGF-I at physiological concentrations retained its full inhibitory effect on atrogin-1/MAFbx mRNA. We conclude that IGF-I inhibits atrogin-1/MAFbx expression and speculate that this effect might contribute to the antiproteolytic action of IGF-I in muscle.