Atrogin-1 affects muscle protein synthesis and degradation when energy metabolism is impaired by the antidiabetes drug berberine.
Atrogin-1 affects muscle protein synthesis and degradation when energy metabolism is impaired by the antidiabetes drug berberine.
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作者：
Wang H;Liu D;Cao P;Lecker S;Hu Z
胰岛素/IGF-1信号缺陷通过抑制蛋白质合成和增加蛋白质降解刺激肌肉蛋白质损失。由于一种草药化合物，小檗碱，降低血糖和血脂水平，我们提出，它将改善胰岛素/IGF-1信号，阻止肌肉蛋白质的损失。我们评估是否小檗碱改善肌肉萎缩的db/db小鼠，2型糖尿病的模型，通过测量蛋白质的合成和降解的正常和db/db小鼠肌肉用或不用小檗碱治疗。我们还研究了小檗碱引起的肌肉蛋白质代谢变化的机制。小檗碱给药降低蛋白质合成，增加正常和db/db小鼠肌肉中的降解。蛋白质分解代谢机制取决于小檗碱刺激的E3遍在蛋白连接酶atrogin-1的表达。Atrogin-1不仅增加蛋白水解，而且通过独立于Akt或叉头转录因子磷酸化降低的机制减少蛋白合成。蛋白质合成受损依赖于eIF 3-f的减少，eIF 3-f是蛋白质合成的重要调节因子。小檗碱损害能量代谢，激活AMP激活的蛋白激酶，并提供了刺激atrogin-1表达的替代机制。当我们通过表达过氧化物酶体增殖物激活受体γ共激活因子-1 α来增加线粒体生物合成时，小檗碱诱导的肌肉蛋白质代谢变化被阻止。黄连素通过两种新机制损害肌肉代谢。它损害线粒体功能，刺激atrogin-1的表达，而不影响叉头转录因子的磷酸化。atrogin-1的增加不仅刺激蛋白质降解，而且抑制蛋白质合成，导致肌肉萎缩。
Defects in insulin/IGF-1 signaling stimulate muscle protein loss by suppressing protein synthesis and increasing protein degradation. Since an herbal compound, berberine, lowers blood levels of glucose and lipids, we proposed that it would improve insulin/IGF-1 signaling, blocking muscle protein losses. We evaluated whether berberine ameliorates muscle atrophy in db/db mice, a model of type 2 diabetes, by measuring protein synthesis and degradation in muscles of normal and db/db mice treated with or without berberine. We also examined mechanisms for berberine-induced changes in muscle protein metabolism. Berberine administration decreased protein synthesis and increased degradation in muscles of normal and db/db mice. The protein catabolic mechanism depended on berberine-stimulated expression of the E3 ubiquitin ligase, atrogin-1. Atrogin-1 not only increased proteolysis but also reduced protein synthesis by mechanisms that were independent of decreased phosphorylation of Akt or forkhead transcription factors. Impaired protein synthesis was dependent on a reduction in eIF3-f, an essential regulator of protein synthesis. Berberine impaired energy metabolism, activating AMP-activated protein kinase and providing an alternative mechanism for the stimulation of atrogin-1 expression. When we increased mitochondrial biogenesis by expressing peroxisome proliferator–activated receptor γ coactivator-1α, berberine-induced changes in muscle protein metabolism were prevented. Berberine impairs muscle metabolism by two novel mechanisms. It impairs mitochonidrial function stimulating the expression of atrogin-1 without affecting phosphorylation of forkhead transcription factors. The increase in atrogin-1 not only stimulated protein degradation but also suppressed protein synthesis, causing muscle atrophy.