Small-molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia.
Small-molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia.
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DOI：
10.1002/jcsm.12233
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Labeit S
中科院分区：
文献类型：
--
作者：
Bowen TS;Adams V;Werner S;Fischer T;Vinke P;Brogger MN;Mangner N;Linke A;Sehr P;Lewis J;Labeit D;Gasch A;Labeit S
肌肉环指1（MuRF 1）是一种肌肉特异性泛素E3连接酶，在与骨骼肌萎缩相关的临床条件下激活。然而，仍然缺乏直接抑制MuRF 1功能的治疗干预，特别是在体内。因此，本研究开发了一种靶向MuRF 1的中央卷曲螺旋结构域的新型化合物，以抑制心脏恶病质中的肌肉萎缩。我们从基于Alpha Technology的130，000种化合物筛选中鉴定出了干扰MuRF 1-肌联蛋白相互作用的小分子。合成了9种优先化合物的子集，并在肌肉萎缩的条件下给药，即给药于用地塞米松处理的C2 C12肌细胞和用野百合碱处理的小鼠以诱导心脏恶病质。所选的9种化合物抑制MuRF 1-肌联蛋白复合，IC 50值<25 μM，发现其中3种化合物还抑制MuRF 1 E3连接酶活性，其中1种化合物进一步显示对培养的肌管的低毒性。最后一种化合物，EMBL化学核心ID#704946，也可预防地塞米松诱导的肌管萎缩，并减轻心脏恶病质期间小鼠的纤维萎缩和收缩功能障碍。蛋白质组学和蛋白质印迹分析显示，ID#704946处理减弱了应激途径，包括MuRF 1的下调以及与凋亡（BAX）和蛋白质合成（eIF 2B-δ）相关的蛋白质的正常化。此外，肌动蛋白泛素化和蛋白酶体活性减弱。我们鉴定了一种针对MuRF 1的中央肌原纤维蛋白识别结构域的新型化合物。该化合物通过保护从头蛋白质合成和下调细胞凋亡和泛素-蛋白酶体依赖性蛋白水解，减轻心脏恶病质中的体内肌肉萎缩和收缩功能障碍。
Muscle ring finger 1 (MuRF1) is a muscle‐specific ubiquitin E3 ligase activated during clinical conditions associated with skeletal muscle wasting. Yet, there remains a paucity of therapeutic interventions that directly inhibit MuRF1 function, particularly in vivo. The current study, therefore, developed a novel compound targeting the central coiled coil domain of MuRF1 to inhibit muscle wasting in cardiac cachexia. We identified small molecules that interfere with the MuRF1–titin interaction from a 130 000 compound screen based on Alpha Technology. A subset of nine prioritized compounds were synthesized and administrated during conditions of muscle wasting, that is, to C2C12 muscle cells treated with dexamethasone and to mice treated with monocrotaline to induce cardiac cachexia. The nine selected compounds inhibited MuRF1–titin complexation with IC50 values <25 μM, of which three were found to also inhibit MuRF1 E3 ligase activity, with one further showing low toxicity on cultured myotubes. This last compound, EMBL chemical core ID#704946, also prevented atrophy in myotubes induced by dexamethasone and attenuated fibre atrophy and contractile dysfunction in mice during cardiac cachexia. Proteomic and western blot analyses showed that stress pathways were attenuated by ID#704946 treatment, including down‐regulation of MuRF1 and normalization of proteins associated with apoptosis (BAX) and protein synthesis (elF2B‐delta). Furthermore, actin ubiquitinylation and proteasome activity was attenuated. We identified a novel compound directed to MuRF1's central myofibrillar protein recognition domain. This compound attenuated in vivo muscle wasting and contractile dysfunction in cardiac cachexia by protecting de novo protein synthesis and by down‐regulating apoptosis and ubiquitin‐proteasome‐dependent proteolysis.
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影响因子：
4.8
作者：
Mrosek, Michael;Labeit, Dietmar;Mayans, Olga
通讯作者：
Mayans, Olga
影响因子：
2.6
作者：
Eddins, Michael J.;Marblestone, Jeffrey G.;Nicholson, Benjamin
通讯作者：
Nicholson, Benjamin
影响因子：
5.5
作者：
Li, Wei;Moylan, Jennifer S.;Reid, Michael B.
通讯作者：
Reid, Michael B.
影响因子：
5.5
作者：
Mayhew, David L.;Hornberger, Troy A.;Bamman, Marcas M.
通讯作者：
Bamman, Marcas M.
DOI：
10.1007/978-1-62703-386-2_4
发表时间：
2013-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Konzer, Anne;Ruhs, Aaron;Kruger, Marcus
通讯作者：
Kruger, Marcus