Miranda Edwin R, Shahtout Justin L, Watanabe Shinya, Milam Norah, Karasawa Takuya, Rout Subhasmita, Atkinson Donald L, Holland William L, Drummond Micah J, Funai Katsuhiko
Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, Utah, USA.
Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, USA.
FASEB J. 2025 Mar 31;39(6):e70464. doi: 10.1096/fj.202402810R.
Immobilization-associated muscle atrophy and weakness appear to be driven in part by oxidative stress. Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) is a critical redox rheostat that regulates oxidative stress responses, and its deletion is known to accelerate muscle atrophy and weakness during aging (sarcopenia) or denervation. Conversely, pharmacologic activation of NRF2 extends mouse lifespan and attenuates sarcopenia. Similarly, deletion of Kelch-like ECH-associated Protein 1 (Keap1), a negative regulator of NRF2, enhances exercise capacity. The purpose of this study was to determine whether muscle-specific Keap1 deletion is sufficient to prevent muscle atrophy and weakness in mice following 7 days of hindlimb unloading (HU). To test this hypothesis, control (Ctrl) and tamoxifen-inducible, muscle-specific Keap1 knockout (mKO) mice were subjected to either normal housing (Sham) or HU for 7 days. Activation of NRF2 in muscle was confirmed by increased mRNA of NRF2 targets thioredoxin 1 (Txn1) and NAD(P)H quinone dehydrogenase 1 (NQO1) in mKO mice. Keap1 deletion had an effect to increase force-generating capacity at baseline. However, muscle masses, cross-sectional area, and ex vivo force were not different between mKO and Ctrl HU mice. In addition, muscle 4-hydroxynonenal-modified proteins and protein carbonyls were unaffected by Keap1 deletion. These data suggest that NRF2 activation improves muscle force production during ambulatory conditions but is not sufficient to prevent muscle atrophy or weakness following 7 days of HU.
固定相关的肌肉萎缩和无力似乎部分由氧化应激驱动。核因子红细胞2相关因子2（NRF2）是一种关键的氧化还原调节剂，可调节氧化应激反应，已知其缺失会加速衰老（肌肉减少症）或去神经支配期间的肌肉萎缩和无力。相反，NRF2的药物激活可延长小鼠寿命并减轻肌肉减少症。同样，NRF2的负调节因子kelch样ECH相关蛋白1（Keap1）的缺失可增强运动能力。本研究的目的是确定肌肉特异性Keap1缺失是否足以预防小鼠后肢卸载（HU）7天后的肌肉萎缩和无力。为了验证这一假设，将对照（Ctrl）和他莫昔芬诱导的肌肉特异性Keap1基因敲除（mKO）小鼠置于正常饲养环境（假手术组）或进行7天的HU。通过mKO小鼠中NRF2靶标硫氧还蛋白1（Txn1）和NAD（P）H醌脱氢酶1（NQO1）的mRNA增加，证实了肌肉中NRF2的激活。Keap1缺失在基线时具有增加力量产生能力的作用。然而，mKO和Ctrl HU小鼠之间的肌肉质量、横截面积和离体力量并无差异。此外，肌肉4-羟基壬烯醛修饰蛋白和蛋白质羰基不受Keap1缺失的影响。这些数据表明，NRF2激活可改善活动状态下的肌肉力量产生，但不足以预防HU 7天后的肌肉萎缩或无力。
