Department of Biology of Physical Activity, Neuromuscular Research Center, University of Jyväskylä, Jyväskylä, Finland.
Am J Physiol Endocrinol Metab. 2012 Feb 1;302(3):E307-15. doi: 10.1152/ajpendo.00398.2011. Epub 2011 Nov 8.
Type 1 diabetes, if poorly controlled, leads to skeletal muscle atrophy, decreasing the quality of life. We aimed to search highly responsive genes in diabetic muscle atrophy in a common diabetes model and to further characterize associated signaling pathways. Mice were killed 1, 3, or 5 wk after streptozotocin or control. Gene expression of calf muscles was analyzed using microarray and protein signaling with Western blotting. We identified translational repressor protein REDD1 (regulated in development and DNA damage responses) that increased seven- to eightfold and was associated with muscle atrophy in diabetes. The diabetes-induced increase in REDD1 was confirmed at the protein level. This result was accompanied by the increased gene expression of DNA damage/repair pathways and decreased expression in ATP production pathways. Concomitantly, increased phosphorylation of AMPK and dephosphorylation of the Akt/mTOR/S6K1/FoxO pathway of proteins were observed together with increased protein ubiquitination. These changes were especially evident during the first 3 wk, along with the strong decrease in muscle mass. Diabetes also induced an increase in myostatin protein and decreased MAPK signaling. These, together with decreased serum insulin and increased serum glucose, remained altered throughout the 5-wk period. In conclusion, diabetic myopathy induced by streptozotocin led to alteration of multiple signaling pathways. Of those, increased REDD1 and myostatin together with decreased Akt/mTOR/FoxO signaling are associated with diabetic muscle atrophy. The increased REDD1 and decreased Akt/mTOR/FoxO signaling followed a similar time course and thus may be explained, in part, by increased expression of genes in DNA damage/repair and possibly also decrease in ATP-production pathways.
1 型糖尿病如果控制不佳，会导致骨骼肌萎缩，降低生活质量。我们旨在搜索普通糖尿病模型中糖尿病肌肉萎缩的高反应性基因，并进一步描述相关信号通路。链脲佐菌素或对照处理后 1、3 或 5 周处死小鼠。使用微阵列分析腓肠肌的基因表达，并使用 Western 印迹进行蛋白质信号转导。我们发现了翻译抑制剂蛋白 REDD1（发育和 DNA 损伤反应调节），其表达增加了七到八倍，并与糖尿病中的肌肉萎缩有关。糖尿病诱导的 REDD1 增加在蛋白质水平上得到了证实。这一结果伴随着 DNA 损伤/修复途径的基因表达增加和 ATP 产生途径的表达降低。同时，还观察到 AMPK 的磷酸化增加和 Akt/mTOR/S6K1/FoxO 途径蛋白的去磷酸化增加，以及蛋白质泛素化增加。这些变化在最初的 3 周内尤为明显，同时肌肉质量也明显下降。糖尿病还诱导肌肉生长抑制素蛋白增加和 MAPK 信号转导降低。这些变化以及血清胰岛素降低和血糖升高在 5 周内一直存在改变。总之，链脲佐菌素诱导的糖尿病性肌病导致了多种信号通路的改变。其中，REDD1 和肌肉生长抑制素的增加以及 Akt/mTOR/FoxO 信号的减少与糖尿病性肌肉萎缩有关。REDD1 的增加和 Akt/mTOR/FoxO 信号的减少遵循相似的时间过程，因此部分可以通过 DNA 损伤/修复和可能还有 ATP 产生途径的表达降低来解释。
