Han Bing, Zhu Mei J, Ma Changwei, Du Min
College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, People's Republic of China.
Appl Physiol Nutr Metab. 2007 Dec;32(6):1115-23. doi: 10.1139/H07-102.
Inactivity is known to induce muscle atrophy, which is associated with insulin and insulin-like growth factor-1 (IGF-1) resistance, but the associated mechanisms remain poorly defined. The hindlimb unloading model has been used to reduce muscle activity. The objective of this study was to show the effect of hindlimb unloading on IGF-1 signaling and AMP-activated protein kinase (AMPK) activity in rat soleus and extensor digitorum longus (EDL) muscles. Twelve 7-week-old male Sprague-Dawley rats were assigned to 2 treatments: (i) rats without hindlimb unloading (Con) and (ii) rats with hindlimb unloading (Unload). After 2 weeks of treatment, the soleus and EDL muscles were dissected and used for biochemical analyses. Hindlimb unloading induced severe muscle atrophy in soleus muscle (0.122+/-0.007 g for Con vs. 0.031+/-0.004 g for Unload, p<0.01), but only slight atrophy in EDL muscle. The phosphorylation of AMPK (p<0.05) and its downstream substrate, acetyl-CoA carboxylase (ACC) (p<0.01) were reduced in soleus muscle due to unloading. The concentration of insulin receptor substrate-1 (IRS-1) and phosphorylation of IRS-1 at Ser636-639 and Ser789 were also reduced. Downstream IGF-1 signaling was downregulated in Unload rats. A reduction in IGF-1 concentration in unloaded soleus muscle was also observed. A slight reduction in AMPK activity and IGF-1 signaling were observed in EDL muscle. Since AMPK controls the sensitivity of IGF-1 signaling through phosphorylation at Ser789, the reduction in AMPK activity is expected to reduce the response of downstream IGF-1 signaling to IGF-1; this, in combination with reduced IGF-1 concentration, might be responsible for the severe muscle atrophy observed in unloaded soleus muscle.
众所周知，缺乏运动可导致肌肉萎缩，这与胰岛素及胰岛素样生长因子-1（IGF-1）抵抗有关，但其相关机制仍不清楚。后肢去负荷模型已被用于减少肌肉活动。本研究的目的是显示后肢去负荷对大鼠比目鱼肌和趾长伸肌（EDL）中IGF-1信号传导及AMP激活的蛋白激酶（AMPK）活性的影响。将12只7周龄雄性Sprague-Dawley大鼠分为2组进行处理：（i）未进行后肢去负荷的大鼠（Con）和（ii）进行后肢去负荷的大鼠（Unload）。处理2周后，解剖比目鱼肌和EDL肌肉用于生化分析。后肢去负荷导致比目鱼肌严重萎缩（Con组为0.122±0.007 g，Unload组为0.031±0.004 g，p<0.01），但EDL肌肉仅有轻微萎缩。去负荷导致比目鱼肌中AMPK的磷酸化（p<0.05）及其下游底物乙酰辅酶A羧化酶（ACC）的磷酸化（p<0.01）降低。胰岛素受体底物-1（IRS-1）的浓度以及IRS-1在Ser636-639和Ser789位点的磷酸化也降低。Unload组大鼠下游IGF-1信号传导下调。在去负荷的比目鱼肌中还观察到IGF-1浓度降低。在EDL肌肉中观察到AMPK活性和IGF-1信号传导略有降低。由于AMPK通过Ser789位点的磷酸化控制IGF-1信号传导的敏感性，预计AMPK活性降低会减少下游IGF-1信号传导对IGF-1的反应；这与IGF-1浓度降低相结合，可能是去负荷比目鱼肌中观察到严重肌肉萎缩的原因。
