Glucocorticoid-dependent REDD1 expression reduces muscle metabolism to enable adaptation under energetic stress.
Glucocorticoid-dependent REDD1 expression reduces muscle metabolism to enable adaptation under energetic stress.
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DOI：
10.1186/s12915-018-0525-4
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发表时间：
2018-06-12
期刊：
影响因子：
5.4
通讯作者：
Favier FB
中科院分区：
文献类型：
--
作者：
Britto FA;Cortade F;Belloum Y;Blaquière M;Gallot YS;Docquier A;Pagano AF;Jublanc E;Bendridi N;Koechlin-Ramonatxo C;Chabi B;Francaux M;Casas F;Freyssenet D;Rieusset J;Giorgetti-Peraldi S;Carnac G;Ollendorff V;Favier FB
骨骼肌萎缩是许多慢性疾病的共同特征，并与患者死亡率相关。目前认为，通过抑制Akt/mTORC1信号通路，REDD1蛋白是肌肉质量的负调节因子。糖皮质激素的分泌可显著诱导REDD1的表达，而糖皮质激素是能量应激反应的一个组成部分。出乎意料的是，我们在这里表明，REDD1反而通过减少糖原消耗和AMPK激活来限制能量应激（如缺氧和禁食）期间的肌肉损失。事实上，我们证明了REDD1是通过减少线粒体相关内质网膜（MAMs）的范围来减少骨骼肌中O2和ATP消耗所必需的，MAMs是连接线粒体和合成代谢过程产生能量的中心枢纽。事实上，在MAMs中，REDD1通过破坏Akt/己糖激酶II和PRAS40/mTORC1信号通路抑制atp需求过程，如糖原储存和蛋白质合成。我们的研究结果揭示了一种新的依赖于redd1的机制，它将线粒体呼吸和缺氧、禁食和运动期间的合成代谢过程耦合在一起。因此，REDD1是能量消耗的一个至关重要的负调节因子，是能量应激时肌肉适应所必需的。本研究可以揭示REDD1在与能量代谢改变相关的几种病理中的作用，如癌症、糖尿病和帕金森病。本文的在线版本（10.1186/s12915-018-0525-4）包含补充材料，仅供授权用户使用。
Skeletal muscle atrophy is a common feature of numerous chronic pathologies and is correlated with patient mortality. The REDD1 protein is currently recognized as a negative regulator of muscle mass through inhibition of the Akt/mTORC1 signaling pathway. REDD1 expression is notably induced following glucocorticoid secretion, which is a component of energy stress responses. Unexpectedly, we show here that REDD1 instead limits muscle loss during energetic stresses such as hypoxia and fasting by reducing glycogen depletion and AMPK activation. Indeed, we demonstrate that REDD1 is required to decrease O2 and ATP consumption in skeletal muscle via reduction of the extent of mitochondrial-associated endoplasmic reticulum membranes (MAMs), a central hub connecting energy production by mitochondria and anabolic processes. In fact, REDD1 inhibits ATP-demanding processes such as glycogen storage and protein synthesis through disruption of the Akt/Hexokinase II and PRAS40/mTORC1 signaling pathways in MAMs. Our results uncover a new REDD1-dependent mechanism coupling mitochondrial respiration and anabolic processes during hypoxia, fasting, and exercise. Therefore, REDD1 is a crucial negative regulator of energy expenditure that is necessary for muscle adaptation during energetic stresses. This present study could shed new light on the role of REDD1 in several pathologies associated with energetic metabolism alteration, such as cancer, diabetes, and Parkinson’s disease. The online version of this article (10.1186/s12915-018-0525-4) contains supplementary material, which is available to authorized users.
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影响因子：
5.7
作者：
Cerniglia GJ;Dey S;Gallagher-Colombo SM;Daurio NA;Tuttle S;Busch TM;Lin A;Sun R;Esipova TV;Vinogradov SA;Denko N;Koumenis C;Maity A
通讯作者：
Maity A
影响因子：
3.7
作者：
Bertrand C;Blanchet E;Pessemesse L;Annicotte JS;Feillet-Coudray C;Chabi B;Levin J;Fajas L;Cabello G;Wrutniak-Cabello C;Casas F
通讯作者：
Casas F
DOI：
10.1002/art.40104
发表时间：
2017-07
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Alvarez-Garcia O;Matsuzaki T;Olmer M;Plate L;Kelly JW;Lotz MK
通讯作者：
Lotz MK
影响因子：
4.4
作者：
Brafman, A;Mett, I;Shoshani, T
通讯作者：
Shoshani, T
影响因子：
29
作者：
Fang Y;Westbrook R;Hill C;Boparai RK;Arum O;Spong A;Wang F;Javors MA;Chen J;Sun LY;Bartke A
通讯作者：
Bartke A