Department of Exercise Science, Syracuse University, NY 13206, USA.
Acta Diabetol. 2010 Dec;47(4):315-23. doi: 10.1007/s00592-010-0209-1. Epub 2010 Jul 17.
Type 1 diabetes mellitus (DM)-induced skeletal muscle atrophy is associated with an increased incidence in morbidity and mortality. Although the precise mechanism of diabetes-induced skeletal muscle atrophy remains to be established, several NF-κB-dependent pro-inflammatory genes have been identified as potential therapeutic targets. Moreover, activation of NF-κB has previously been shown to be required for cytokine-induced loss of skeletal muscle proteins. Therefore, we investigated activation of the NF-κB canonical pathway, concomitant to insulin signaling activation in skeletal muscle from diabetes-induced rats. Ten rats injected with streptozotocin (STZ) 4 weeks prior to tissue extraction were compared to 10 control rats. Using total, cytosolic and nuclear protein extracts from hindlimb muscles: soleus (SOL), extensor digitorum longus (EDL), gastrocnemius (GM) and liver tissue, we assessed key proteins important for the activation of both NF-κB and insulin pathways. Insulin blood concentration decreased to 3.9 ± 1.2 mU/ml following STZ-injection resulting in hyperglycemia (17.9 ± 0.7 mmol/l). SOL, EDL and GM mass decreased, and liver mass increased following STZ injection. NF-κB/p65 content in SOL, GM and liver increased in STZ-injected rats, without any change in IκB degradation or IKK phosphorylation. Muscle NF-κB/p65 remained bound to IκB and did not translocate or bind to DNA. Although the canonical NF-κB cascade was not activated, STZ induced a decrease in insulin pathway proteins including insulin receptor (IR) and substrate (IRS-1) content and phosphorylation compared to control animals. A downregulation of insulin pathway proteins and muscle atrophy occurred in response to STZ administration, and despite increased p65 content, STZ treatment did not activate the canonical NF-κB cascade. Therefore, it is unlikely that hyperglycemia initiates skeletal muscle atrophy via activation of the NF-κB canonical pathway.
1 型糖尿病（DM）引起的骨骼肌萎缩与发病率和死亡率的增加有关。尽管糖尿病引起的骨骼肌萎缩的确切机制尚待确定，但已经确定了几种 NF-κB 依赖性促炎基因作为潜在的治疗靶点。此外，先前已经表明 NF-κB 的激活对于细胞因子诱导的骨骼肌蛋白丢失是必需的。因此，我们研究了糖尿病诱导的大鼠骨骼肌中胰岛素信号激活同时 NF-κB 经典途径的激活。在组织提取前 4 周注射链脲佐菌素（STZ）的 10 只大鼠与 10 只对照大鼠进行了比较。使用来自后肢肌肉（比目鱼肌、趾长伸肌、腓肠肌和肝组织）的总、胞质和核蛋白提取物，我们评估了对 NF-κB 和胰岛素途径激活都很重要的关键蛋白。STZ 注射后，胰岛素血液浓度降至 3.9±1.2mU/ml，导致高血糖（17.9±0.7mmol/l）。注射 STZ 后，比目鱼肌、趾长伸肌和腓肠肌质量下降，肝质量增加。注射 STZ 后，大鼠比目鱼肌、腓肠肌和肝组织中 NF-κB/p65 含量增加，但 IκB 降解或 IKK 磷酸化没有变化。肌肉 NF-κB/p65 仍然与 IκB 结合，没有易位或与 DNA 结合。尽管经典 NF-κB 级联没有被激活，但与对照动物相比，STZ 诱导胰岛素途径蛋白包括胰岛素受体（IR）和底物（IRS-1）含量和磷酸化减少。STZ 给药后，胰岛素途径蛋白和肌肉萎缩下调，尽管 p65 含量增加，但 STZ 治疗并未激活经典 NF-κB 级联。因此，高血糖不太可能通过激活 NF-κB 经典途径引发骨骼肌萎缩。
