Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase.
Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase.
复制标题
通过抑制DSRNA依赖性蛋白激酶，在恶病质鼠模型中肌肉萎缩的衰减。
DOI：
10.1038/sj.bjc.6603704
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发表时间：
2007-04-23
影响因子：
8.8
通讯作者：
Tisdale, M J
中科院分区：
文献类型：
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作者：
Eley, H L;Russell, S T;Tisdale, M J
骨骼肌的萎缩是由于蛋白质合成的抑制和降解的增加。体外研究表明，dsrna依赖性蛋白激酶（PKR）的激活可能是导致这些蛋白质合成和降解变化的原因。为了评估这是否也适用于癌症恶病质，我们在携带MAC16肿瘤的小鼠中研究了PKR抑制剂对恶病质发展的作用。PKR抑制剂（5mg kg - 1）显著降低了动物肌肉中磷酸化PKR的水平，使其降至非荷瘤小鼠的水平，并有效减轻了体重的抑制，增加了肌肉质量，还抑制了肿瘤的生长。骨骼肌中蛋白质合成增加，与真核起始因子2α磷酸化减少相一致。骨骼肌中的蛋白质降解率也显著降低，蛋白酶体活性水平和表达也显著降低。肌球蛋白水平升高到非荷瘤动物的水平。蛋白酶体表达与核因子-κB （NF-κB）核积累减少相关。PKR抑制剂也显著抑制肿瘤生长，尽管这似乎与对肌肉萎缩的影响是单独的事件。这些结果表明，抑制PKR的自磷酸化可能是癌症恶病质中肌肉萎缩衰减的合适靶点。
Atrophy of skeletal muscle is due to a depression in protein synthesis and an increase in degradation. Studies in vitro have suggested that activation of the dsRNA-dependent protein kinase (PKR) may be responsible for these changes in protein synthesis and degradation. In order to evaluate whether this is also applicable to cancer cachexia the action of a PKR inhibitor on the development of cachexia has been studied in mice bearing the MAC16 tumour. Treatment of animals with the PKR inhibitor (5 mg kg−1) significantly reduced levels of phospho-PKR in muscle down to that found in non-tumour-bearing mice, and effectively attenuated the depression of body weight, with increased muscle mass, and also inhibited tumour growth. There was an increase in protein synthesis in skeletal muscle, which paralleled a decrease in eukaryotic initiation factor 2α phosphorylation. Protein degradation rates in skeletal muscle were also significantly decreased, as was proteasome activity levels and expression. Myosin levels were increased up to values found in non-tumour-bearing animals. Proteasome expression correlated with a decreased nuclear accumulation of nuclear factor-κB (NF-κB). The PKR inhibitor also significantly inhibited tumour growth, although this appeared to be a separate event from the effect on muscle wasting. These results suggest that inhibition of the autophosphorylation of PKR may represent an appropriate target for the attenuation of muscle atrophy in cancer cachexia.