Alcohol Acutely Antagonizes Refeeding-Induced Alterations in the Rag GTPase-Ragulator Complex in Skeletal Muscle.
Alcohol Acutely Antagonizes Refeeding-Induced Alterations in the Rag GTPase-Ragulator Complex in Skeletal Muscle.
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DOI：
10.3390/nu13041236
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发表时间：
2021-04-09
期刊：
影响因子：
5.9
通讯作者：
Lang CH
中科院分区：
文献类型：
--
作者：
Laufenberg LJ;Crowell KT;Lang CH
Ragator蛋白复合体是将Rag GTPase蛋白和mTORC1定向到溶酶体膜，介导氨基酸刺激的蛋白质合成的关键。由于缺乏证据表明酒精对Rag-Ragator复合体的影响是酒精性骨骼肌萎缩的可能机制，本研究的目的是研究在摄食过程中急性产生的Rag-Ragator途径中各种蛋白质-蛋白质复合体的变化，以及在活体条件下酒精是如何改变这些变化的。小鼠(C57BL/6；成年雄性)禁食，然后给予啮齿动物食物30min(“Reed”)或继续禁食(“Fasted”)。小鼠随后给予乙醇(3g/kg乙醇)或生理盐水，1h后采集后肢肌肉进行分析。酒精可抑制再摄食诱导的肌原纤维和肌浆蛋白合成的增加以及mTOR和S6K1的磷酸化。这种抑制与细胞内亮氨酸浓度或血浆亮氨酸或胰岛素水平的差异升高无关。酒精增加了禁食状态下Sestrin1·GATOR2复合体的数量，并阻止了再喂养引起的对照组小鼠Sestrin1·GATOR2的减少。乙醇能拮抗REFED状态下RAGA/C·Raptor复合体形成的增加。酒精可拮抗重新摄食后免疫沉淀的LAMPTOR1(Ragator复合体的一部分)对Raptor的增加，并降低RagC与LAMPTOR1的联系。最后，酒精增加了v-ATPase的V1结构域与LAMPTOR1的结合，并阻止了再摄食引起的v-ATPase V1与LAMPTOR1的结合。总体而言，这些数据表明，急性酒精摄入扰乱了Rag-Ragator复合体中的多个蛋白质-蛋白质复合体，这些复合体与体内条件下营养刺激的肌肉蛋白质合成的伴随下降有关并一致。
The Ragulator protein complex is critical for directing the Rag GTPase proteins and mTORC1 to the lysosome membrane mediating amino acid-stimulated protein synthesis. As there is a lack of evidence on alcohol’s effect on the Rag-Ragulator complex as a possible mechanism for the development of alcoholic skeletal muscle wasting, the aim of our study was to examine alterations in various protein–protein complexes in the Rag-Ragulator pathway produced acutely by feeding and how these are altered by alcohol under in vivo conditions. Mice (C57Bl/6; adult males) were fasted, and then provided rodent chow for 30 min (“refed”) or remained food-deprived (“fasted”). Mice subsequently received ethanol (3 g/kg ethanol) or saline intraperitoneally, and hindlimb muscles were collected 1 h thereafter for analysis. Refeeding-induced increases in myofibrillar and sarcoplasmic protein synthesis, and mTOR and S6K1 phosphorylation, were prevented by alcohol. This inhibition was not associated with a differential rise in the intracellular leucine concentration or plasma leucine or insulin levels. Alcohol increased the amount of the Sestrin1•GATOR2 complex in the fasted state and prevented the refeeding-induced decrease in Sestrin1•GATOR2 seen in control mice. Alcohol antagonized the increase in the RagA/C•Raptor complex formation seen in the refed state. Alcohol antagonized the increase in Raptor with immunoprecipitated LAMPTOR1 (part of the Ragulator complex) after refeeding and decreased the association of RagC with LAMPTOR1. Finally, alcohol increased the association of the V1 domain of v-ATPase with LAMPTOR1 and prevented the refeeding-induced decrease in v-ATPase V1 with LAMPTOR1. Overall, these data demonstrate that acute alcohol intake disrupts multiple protein–protein complexes within the Rag-Ragulator complex, which are associated with and consistent with the concomitant decline in nutrient-stimulated muscle protein synthesis under in vivo conditions.
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影响因子：
8.8
作者：
Chantranupong L;Wolfson RL;Orozco JM;Saxton RA;Scaria SM;Bar-Peled L;Spooner E;Isasa M;Gygi SP;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
4.8
作者：
Meng, Delong;Yang, Qianmei;Jewell, Jenna L.
通讯作者：
Jewell, Jenna L.
DOI：
10.1097/00000374-200003000-00010
发表时间：
2000-03-01
影响因子：
3.2
作者：
Lang, CH;Frost, RA;Vary, TC
通讯作者：
Vary, TC
影响因子：
4.2
作者：
Lang, Charles H.;Lynch, Christopher J.;Vary, Thomas C.
通讯作者：
Vary, Thomas C.
DOI：
10.1073/pnas.1801287115
发表时间：
2018-06-05
影响因子：
11.1
作者：
Lee, Minji;Kim, Jong Hyun;Han, Jung Min
通讯作者：
Han, Jung Min