Resistance training recovers attenuated APPL1 expression and improves insulin-induced Akt signal activation in skeletal muscle of type 2 diabetic rats
Resistance training recovers attenuated APPL1 expression and improves insulin-induced Akt signal activation in skeletal muscle of type 2 diabetic rats
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DOI：
10.1152/ajpendo.00362.2017
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发表时间：
2018-06-01
影响因子：
5.1
通讯作者：
Fujita, Satoshi
中科院分区：
文献类型：
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作者：
Kido, Kohei;Ato, Satoru;Fujita, Satoshi
含有Pleckstrin同源(PH)结构域、磷酸酪氨酸结合(PTB)结构域的适配蛋白。而亮氨酸拉链基序1(APPL1)已被报道为胰岛素刺激Akt激活的正调节因子。APPL1在2型糖尿病(T2D)动物骨骼肌中的表达降低，提示APPL1可能是影响胰岛素敏感性的重要因素。然而，APPL1表达的调节以及调节这些效应的生理干预尚不清楚。因此，我们首次证实APPL1的表达和胰岛素诱导的Akt磷酸化在T2D大鼠的骨骼肌中显著减弱。此外，我们发现APPL1的表达水平与空腹血糖水平显著相关。接下来，我们确定了参与APPL1表达的重要信号。AMP活化的蛋白激酶、钙离子、p38丝裂原活化的蛋白激酶和胰岛素样生长因子-1信号激活后，APPL1的mRNA表达增加。此外，体内急性抗阻运动显著激活了这些信号通路。最后，通过体内实验，我们发现慢性阻力训练(RT)增加了APPL1的表达，并激活了胰岛素诱导的T2D大鼠骨骼肌Akt信号。此外，在相同条件下，APPL1表达的变化(即对照肌肉和RT肌肉之间的差异)与胰岛素刺激的Akt磷酸化的变化显著相关。因此，慢性RT可恢复T2D大鼠骨骼肌APPL1的表达，改善胰岛素刺激的Akt磷酸化。因此，APPL1可能是骨骼肌胰岛素抵抗的关键调节因子，RT可能是增加APPL1表达的重要生理治疗，而APPL1在T2D中被减弱。
Adapter protein containing Pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain. and leucine zipper motif 1 (APPL1) has been reported as a positive regulator of insulin-stimulated Akt activation. The expression of APPL1 is reduced in skeletal muscles of type 2 diabetic (T2D) animals, implying that APPL1 may be an important factor affecting insulin sensitivity. However, the regulation of APPL1 expression and the physiological interventions modulating these effects are unclear. Accordingly, we first confirmed that APPL1 expression and insulin-induced Akt phosphorylation were significantly attenuated in skeletal muscles of T2D rats. Additionally, we found that APPL1 expression levels were significantly correlated with fasting blood glucose levels. Next, we identified important signals involved in the expression of APPL1. APPL1 mRNA expression increased upon AMP-activated protein kinase, calcium, p38 mitogen-activated protein kinase, and insulin-like growth factor-1 signal activation. Moreover, acute resistance exercise in vivo significantly activated these signaling pathways. Finally, through in vivo experiments, we found that chronic resistance training (RT) increased APPL1 expression and activated insulin-induced Akt signaling in skeletal muscles of rats with T2D. Furthermore, variations in APPL1 expression (i.e., the difference between control and RT muscles) significantly correlated with variations in insulin-stimulated Akt phosphorylation under the same conditions. Therefore, chronic RT recovered attenuated APPL1 expression and improved insulin-stimulated Akt phosphorylation in skeletal muscles of T2D rats. Accordingly, APPL1 may be a key regulator of insulin resistance in skeletal muscle, and RT may be an important physiological treatment increasing APPL1 expression, which is attenuated in T2D.