Disruption of either the Nfkb1 or the Bcl3 gene inhibits skeletal muscle atrophy
Disruption of either the Nfkb1 or the Bcl3 gene inhibits skeletal muscle atrophy
复制标题
DOI：
10.1172/jci200421696
复制
发表时间：
2004-11-01
影响因子：
15.9
通讯作者：
Kandarian, SC
中科院分区：
文献类型：
--
作者：
Hunter, RB;Kandarian, SC
细胞内信号介导骨骼肌蛋白质损失和功能缺陷，由于肌肉废用才刚刚开始被阐明。以前我们发现，NF-κ B依赖的报告基因的活性显着增加，在卸载肌肉，p50和Bcl-3蛋白参与了这种诱导。在本研究中，敲除p105/p50（Nfkb 1）基因的小鼠显示出对10天后肢卸载导致的比目鱼肌纤维横截面积减少具有抗性。此外，在来自WT小鼠的比目鱼肌中显著的卸载诱导的NF-κ B报告基因的激活在来自Nfkbl敲除小鼠的比目鱼肌中完全消除。敲除B细胞淋巴瘤3（Bcl 3）基因也显示出对纤维萎缩的抑制和NF-κ B报告活性的消除。随着卸载，WT小鼠的快纤维比慢纤维萎缩的程度更大。在两种基因敲除小鼠品系中，快速纤维清楚地显示出对萎缩的抵抗，而仅来自Bcl 3（-/-）小鼠的慢速纤维显示出萎缩抑制。在Nfkb 1和Bcl 3基因敲除小鼠中，由于卸载而导致的肌球蛋白亚型表达的慢到快的转变也被废除。与比目鱼肌一样，来自Nfkb 1（-/-）和Bcl 3（-/-）小鼠的跖肌也显示出对萎缩的抑制。因此，Nfkb 1和Bcl 3基因对于卸载诱导的萎缩和相关的表型转变都是必需的。
The intracellular signals that mediate skeletal muscle protein loss and functional deficits due to muscular disuse are just beginning to be elucidated. Previously we showed that the activity of an NF-kappaB-dependent reporter gene was markedly increased in unloaded muscles, and p50 and Bcl-3 proteins were implicated in this induction. In the present study, mice with a knockout of the p105/p50 (Nfkb1) gene are shown to be resistant to the decrease in soleus fiber cross-sectional area that results from 10 days of hindlimb unloading. Furthermore, the marked unloading-induced activation of the NF-kappaB reporter gene in soleus muscles from WT mice was completely abolished in soleus muscles from Nfkbl knockout mice. Knockout of the B cell lymphoma 3 (Bcl3) gene also showed an inhibition of fiber atrophy and an abolition of NF-kappaB reporter activity. With unloading, fast fibers from WT mice atrophied to a greater extent than slow fibers. Resistance to atrophy in both strains of knockout mice was demonstrated clearly in fast fibers, while slow fibers from only the Bcl3(-/-) mice showed atrophy inhibition. The slow-to-fast shift in myosin isoform expression due to unloading was also abolished in both Nfkb1 and Bcl3 knockout mice. Like the soleus muscles, plantaris muscles from Nfkb1(-/-) and Bcl3(-/-) mice also showed inhibition of atrophy with unloading. Thus both the Nfkbl and the Bcl3 genes are necessary for unloading-induced atrophy and the associated phenotype transition.