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首页> 外文期刊>Cell discovery. >Evidence that S6K1, but not 4E-BP1, mediates skeletal muscle pathology associated with loss of A-type lamins
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Evidence that S6K1, but not 4E-BP1, mediates skeletal muscle pathology associated with loss of A-type lamins

机译：S6K1而不是4E-BP1介导与A型lamin丢失有关的骨骼肌病理的证据

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The mechanistic target of rapamycin (mTOR) signaling pathway plays a central role in aging and a number of different disease states. Rapamycin, which suppresses activity of the mTOR complex 1 (mTORC1), shows preclinical (and sometimes clinical) efficacy in a number of disease models. Among these are Lmna ?/? mice, which serve as a mouse model for dystrophy-associated laminopathies. To confirm that elevated mTORC1 signaling is responsible for the pathology manifested in Lmna ?/? mice and to decipher downstream genetic mechanisms underlying the benefits of rapamycin, we tested in Lmna ?/? mice whether survival could be extended and disease pathology suppressed either by reduced levels of S6K1 or enhanced levels of 4E-BP1, two canonical mTORC1 substrates. Global heterozygosity for S6K1 ubiquitously extended lifespan of Lmna ?/? mice ( Lmna ?/? S6K1 +/? mice). This life extension is due to improving muscle, but not heart or adipose, function, consistent with the observation that genetic ablation of S6K1 specifically in muscle tissue also extended survival of Lmna ?/? mice. In contrast, whole-body overexpression of 4E-BP1 shortened the survival of Lmna ?/? mice, likely by accelerating lipolysis. Thus, rapamycin-mediated lifespan extension in Lmna ?/? mice is in part due to the improvement of skeletal muscle function and can be phenocopied by reduced S6K1 activity, but not 4E-BP1 activation.
机译：雷帕霉素（mTOR）信号传导途径的机械靶标在衰老和许多不同疾病状态中起着核心作用。雷帕霉素抑制mTOR复合物1（mTORC1）的活性，在许多疾病模型中均显示出临床前（有时是临床）功效。其中有Lmna ？/？ 小鼠，可作为营养不良相关的laminopathies的小鼠模型。确认升高的mTORC1信号是Lmna ？/？表现出的病理的原因。 小鼠，并为了阐明雷帕霉素益处的潜在下游遗传机制，我们在Lmna ？/？中进行了测试。 小鼠是否可以通过降低S6K1的水平或提高4E-BP1的水平（两种典型的mTORC1底物）来延长生存期并抑制疾病病理。 S6K1的全球杂合性普遍延长了Lmna的寿命。 小鼠（Lmna ？/？ S6K1 + /？小鼠）。这种延长寿命是由于改善了肌肉而不是心脏或脂肪的功能，这与以下观察结果一致：S6K1特异性消融在肌肉组织中的遗传消融也延长了Lmna的存活。 小鼠。相反，全身过度表达4E-BP1缩短了Lmna的存活率。 小鼠，可能是通过加速脂肪分解。因此，雷帕霉素介导的Lmna的寿命延长。 小鼠的部分原因是骨骼肌功能的改善，可以通过降低S6K1活性（而不是4E-BP1激活）来表型复制。

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