The transcription regulator ATF4 is a mediator of skeletal muscle aging.
The transcription regulator ATF4 is a mediator of skeletal muscle aging.
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DOI：
10.1007/s11357-023-00772-y
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发表时间：
2023-08
期刊：
影响因子：
5.6
通讯作者：
Adams, Christopher M.
中科院分区：
文献类型：
--
作者：
Miller, Matthew J.;Marcotte, George R.;Basisty, Nathan;Wehrfritz, Cameron;Ryan, Zachary C.;Strub, Matthew D.;McKeen, Andrew T.;Stern, Jennifer I.;Nath, Karl A.;Rasmussen, Blake B.;Judge, Andrew R.;Schilling, Birgit;Ebert, Scott M.;Adams, Christopher M.
衰老缓慢地侵蚀骨骼肌的力量和质量，最终导致严重的功能缺陷和肌肉萎缩。骨骼肌衰老的分子机制还不清楚。为了更好地了解肌肉衰老的机制，我们研究了ATF 4的潜在作用，ATF 4是一种转录调节蛋白，可以迅速促进缺乏足够营养或活动的年轻动物骨骼肌萎缩。为了验证ATF 4可能参与骨骼肌衰老的假设，我们研究了6个月龄时的进食和活动肌肉特异性ATF 4敲除小鼠（ATF 4 mKO小鼠），此时野生型小鼠已达到峰值肌肉质量和功能，以及22个月龄时野生型小鼠已开始表现出年龄相关的肌肉萎缩和无力。我们发现6个月大的ATF 4 mKO小鼠发育正常，与6个月大的同窝对照小鼠在表型上无法区分。然而，随着ATF 4 mKO小鼠年龄的增长，它们表现出明显的保护作用，免受年龄相关的力量、肌肉质量、运动能力和肌肉质量下降的影响。此外，ATF 4 mKO肌肉被保护免受正常肌肉衰老的一些转录变化特征（某些合成代谢mRNA的抑制和某些衰老相关mRNA的诱导），并且ATF 4 mKO肌肉表现出在骨骼肌结构和代谢中具有重要作用的几种蛋白质的改变的周转。总的来说，这些数据表明ATF 4是骨骼肌衰老的重要介质，并为损害许多老年人健康和生活质量的退行性过程提供了新的见解。在线版本包含补充材料，可通过10.1007/s11357-023-00772-y获得。
Aging slowly erodes skeletal muscle strength and mass, eventually leading to profound functional deficits and muscle atrophy. The molecular mechanisms of skeletal muscle aging are not well understood. To better understand mechanisms of muscle aging, we investigated the potential role of ATF4, a transcription regulatory protein that can rapidly promote skeletal muscle atrophy in young animals deprived of adequate nutrition or activity. To test the hypothesis that ATF4 may be involved in skeletal muscle aging, we studied fed and active muscle-specific ATF4 knockout mice (ATF4 mKO mice) at 6 months of age, when wild-type mice have achieved peak muscle mass and function, and at 22 months of age, when wild-type mice have begun to manifest age-related muscle atrophy and weakness. We found that 6-month-old ATF4 mKO mice develop normally and are phenotypically indistinguishable from 6-month-old littermate control mice. However, as ATF4 mKO mice become older, they exhibit significant protection from age-related declines in strength, muscle quality, exercise capacity, and muscle mass. Furthermore, ATF4 mKO muscles are protected from some of the transcriptional changes characteristic of normal muscle aging (repression of certain anabolic mRNAs and induction of certain senescence-associated mRNAs), and ATF4 mKO muscles exhibit altered turnover of several proteins with important roles in skeletal muscle structure and metabolism. Collectively, these data suggest ATF4 as an essential mediator of skeletal muscle aging and provide new insight into a degenerative process that impairs the health and quality of life of many older adults. The online version contains supplementary material available at 10.1007/s11357-023-00772-y.
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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