In vivo characterization of the role of tissue-specific translation elongation factor 1A2 in protein synthesis reveals insights into muscle atrophy.
In vivo characterization of the role of tissue-specific translation elongation factor 1A2 in protein synthesis reveals insights into muscle atrophy.
复制标题
DOI：
10.1111/febs.12554
复制
发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Abbott CM
中科院分区：
文献类型：
--
作者：
Doig J;Griffiths LA;Peberdy D;Dharmasaroja P;Vera M;Davies FJ;Newbery HJ;Brownstein D;Abbott CM
翻译延伸因子1A2(EEF1A2)是翻译因子中唯一的一种，在神经元和肌肉中特异表达。EEF1A2突变缺失的废弃小鼠会发展出一种侵袭性的、早发性的神经退化形式，但尚不清楚这种萎缩是由于肌肉失神经所致，还是小鼠患有原发肌病是由于肌肉翻译活动的丧失造成的。我们开始建立不同组织中eEF1A2缺失对这种出生后致死表型的相对贡献。我们使用组织特异性转基因来表明，纠正肌肉中的eEF1A2水平未能改善废弃小鼠的明显表型异常或死亡时间。无论是否存在肌肉特异性eEF1A2表达，肌肉萎缩的分子标志物如Fbxo32在RNA水平上都显著上调，但在那些肌肉中没有转基因表达的废弃小鼠，蛋白质水平上的上调程度明显较低。这第一次在体内证实了eEF1A2在翻译中发挥着重要作用。尽管非转基因废弃小鼠不能像转基因小鼠那样在蛋白质水平上上调关键的营养因子，但在体重减轻、握力或肌肉病理方面，转基因和非转基因废弃小鼠之间没有可测量的差异。这表明，在失神经肌肉中完全执行萎缩基因途径的能力受损在短期内不会影响肌肉萎缩的过程。
Translation elongation factor 1A2 (eEF1A2), uniquely among translation factors, is expressed specifically in neurons and muscle. eEF1A2‐null mutant wasted mice develop an aggressive, early‐onset form of neurodegeneration, but it is unknown whether the wasting results from denervation of the muscles, or whether the mice have a primary myopathy resulting from loss of translation activity in muscle. We set out to establish the relative contributions of loss of eEF1A2 in the different tissues to this postnatal lethal phenotype. We used tissue‐specific transgenesis to show that correction of eEF1A2 levels in muscle fails to ameliorate the overt phenotypic abnormalities or time of death of wasted mice. Molecular markers of muscle atrophy such as Fbxo32 were dramatically upregulated at the RNA level in wasted mice, both in the presence and in the absence of muscle‐specific expression of eEF1A2, but the degree of upregulation at the protein level was significantly lower in those wasted mice without transgene‐derived expression of eEF1A2 in muscle. This provides the first in vivo confirmation that eEF1A2 plays an important role in translation. In spite of the inability of the nontransgenic wasted mice to upregulate key atrogenes at the protein level in response to denervation to the same degree as their transgenic counterparts, there were no measurable differences between transgenic and nontransgenic wasted mice in terms of weight loss, grip strength, or muscle pathology. This suggests that a compromised ability fully to execute the atrogene pathway in denervated muscle does not affect the process of muscle atrophy in the short term.
登录
查看更多内容
影响因子：
3.7
作者：
Mo, Kaiguo;Razak, Zak;Monks, D. Ashley
通讯作者：
Monks, D. Ashley
影响因子：
3.5
作者：
Maddatu, TP;Garvey, SM;Cox, GA
通讯作者：
Cox, GA
DOI：
10.1093/jnen/64.4.295
发表时间：
2005-04-01
影响因子：
3.2
作者：
Newbery, HJ;Gillingwater, TH;Abbott, CM
通讯作者：
Abbott, CM
影响因子：
64.8
作者：
SHULTZ, LD;SWEET, HO;COMAN, DR
通讯作者：
COMAN, DR
影响因子：
14.9
作者：
Kahns, S;Lund, A;Merrick, WC
通讯作者：
Merrick, WC