Ligand-induced rapid skeletal muscle atrophy in HSA-Fv2E-PERK transgenic mice.
Ligand-induced rapid skeletal muscle atrophy in HSA-Fv2E-PERK transgenic mice.
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DOI：
10.1371/journal.pone.0179955
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Oyadomari S
中科院分区：
文献类型：
--
作者：
Miyake M;Kuroda M;Kiyonari H;Takehana K;Hisanaga S;Morimoto M;Zhang J;Oyadomari M;Sakaue H;Oyadomari S
43S和48S起始前复合物的形成在肌肉蛋白质合成中起重要作用。目前还没有因43S起始前复合物组装受抑制而导致的肌肉萎缩小鼠模型。
本研究的目的是建立一种43S起始前复合物组装受抑制的方便的骨骼肌萎缩小鼠模型。
一种配体激活型PERK衍生物Fv2E - PERK可导致真核起始因子2α（eIF2α）磷酸化，从而抑制43S起始前复合物组装。因此，在人骨骼肌α - 肌动蛋白（HSA）启动子驱动的Fv2E - PERK转基因（Tg）小鼠中研究了肌肉萎缩表型、细胞内信号通路以及细胞内游离氨基酸谱。
用人造二聚体AP20187处理的HSA - Fv2E - PERK转基因小鼠可使骨骼肌中的eIF2α磷酸化，并在注射配体后的几天内导致严重的肌肉萎缩。肌肉萎缩伴随着mTORC1信号通路的反向调节性激活。此外，HSA - Fv2E - PERK转基因小鼠骨骼肌中的细胞内游离氨基酸水平发生了明显变化。
作为一种新的肌肉萎缩模型，HSA - Fv2E - PERK转基因小鼠为研究肌肉损失的发病机制以及评估潜在的治疗方法提供了一种便捷的工具。
Formation of 43S and 48S preinitiation complexes plays an important role in muscle protein synthesis. There is no muscle-wasting mouse model caused by a repressed 43S preinitiation complex assembly. The aim of the present study was to develop a convenient mouse model of skeletal muscle wasting with repressed 43S preinitiation complex assembly. A ligand-activatable PERK derivative Fv2E-PERK causes the phosphorylation of eukaryotic initiation factor 2α (eIF2α), which inhibits 43S preinitiation complex assembly. Thus, muscle atrophic phenotypes, intracellular signaling pathways, and intracellular free amino acid profiles were investigated in human skeletal muscle α-actin (HSA) promoter-driven Fv2E-PERK transgenic (Tg) mice. HSA-Fv2E-PERK Tg mice treated with the artificial dimerizer AP20187 phosphorylates eIF2α in skeletal muscles and leads to severe muscle atrophy within a few days of ligand injection. Muscle atrophy was accompanied by a counter regulatory activation of mTORC1 signaling. Moreover, intracellular free amino acid levels were distinctively altered in the skeletal muscles of HSA-Fv2E-PERK Tg mice. As a novel model of muscle wasting, HSA-Fv2E-PERK Tg mice provide a convenient tool for studying the pathogenesis of muscle loss and for assessing putative therapeutics.