Department of Neurobiology, Physiology, and Behavior, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA.
J Physiol. 2011 Oct 1;589(Pt 19):4759-76. doi: 10.1113/jphysiol.2011.212845. Epub 2011 Aug 1.
Skeletal muscle atrophy occurs under a variety of conditions and can result from alterations in both protein synthesis and protein degradation. The muscle-specific E3 ubiquitin ligases, MuRF1 and MAFbx, are excellent markers of muscle atrophy and increase under divergent atrophy-inducing conditions such as denervation and glucocorticoid treatment. While deletion of MuRF1 or MAFbx has been reported to spare muscle mass following 14 days of denervation, their role in other atrophy-inducing conditions is unclear. The goal of this study was to determine whether deletion of MuRF1 or MAFbx attenuates muscle atrophy after 2 weeks of treatment with the synthetic glucocorticoid dexamethasone (DEX). The response of the triceps surae (TS) and tibialis anterior (TA) muscles to 14 days of DEX treatment (3 mg kg(-1) day(-1)) was examined in 4 month-old male and female wild type (WT) and MuRF1 or MAFbx knock out (KO) mice. Following 14 days of DEX treatment, muscle wet weight was significantly decreased in the TS and TA of WT mice. Comparison of WT and KO mice following DEX treatment revealed significant sparing of mass in both sexes of the MuRF1 KO mice, but no muscle sparing in MAFbx KO mice. Further analysis of the MuRF1 KO mice showed significant sparing of fibre cross-sectional area and tension output in the gastrocnemius (GA) after DEX treatment. Muscle sparing in the MuRF1 KO mice was related to maintenance of protein synthesis, with no observed increases in protein degradation in either WT or MuRF1 KO mice. These results demonstrate that MuRF1 and MAFbx do not function similarly under all atrophy models, and that the primary role of MuRF1 may extend beyond controlling protein degradation via the ubiquitin proteasome system.
骨骼肌萎缩发生在多种情况下，可能是由于蛋白质合成和蛋白质降解的改变。肌肉特异性 E3 泛素连接酶 MuRF1 和 MAFbx 是肌肉萎缩的极好标志物，在去神经和糖皮质激素治疗等不同的萎缩诱导条件下增加。虽然 MuRF1 或 MAFbx 的缺失已被报道在去神经 14 天后可保留肌肉质量，但它们在其他萎缩诱导条件下的作用尚不清楚。本研究的目的是确定 MuRF1 或 MAFbx 的缺失是否会减轻合成糖皮质激素地塞米松 (DEX) 治疗 2 周后的肌肉萎缩。在 4 月龄雄性和雌性野生型 (WT) 和 MuRF1 或 MAFbx 敲除 (KO) 小鼠中，检查了后肢三头肌 (TS) 和胫骨前肌 (TA) 对 14 天 DEX 治疗 (3mgkg(-1)day(-1)) 的反应。DEX 治疗 14 天后，WT 小鼠的 TS 和 TA 肌肉湿重显著降低。DEX 治疗后 WT 和 KO 小鼠的比较显示，雄性和雌性 MuRF1 KO 小鼠的质量均有明显保留，但 MAFbx KO 小鼠没有。对 MuRF1 KO 小鼠的进一步分析表明，DEX 治疗后，比目鱼肌 (GA) 的纤维横截面积和张力输出有明显保留。MuRF1 KO 小鼠的肌肉保留与蛋白质合成的维持有关，在 WT 或 MuRF1 KO 小鼠中均未观察到蛋白质降解的增加。这些结果表明，MuRF1 和 MAFbx 在所有萎缩模型下的作用并不相同，并且 MuRF1 的主要作用可能超出通过泛素蛋白酶体系统控制蛋白质降解的范围。
