Targeting the Ubiquitin E3 Ligase MuRF1 to Inhibit Muscle Atrophy
Targeting the Ubiquitin E3 Ligase MuRF1 to Inhibit Muscle Atrophy
复制标题
DOI：
10.1007/s12013-011-9175-7
复制
发表时间：
2011-06-01
影响因子：
2.6
通讯作者：
Nicholson, Benjamin
中科院分区：
文献类型：
--
作者：
Eddins, Michael J.;Marblestone, Jeffrey G.;Nicholson, Benjamin
进行性肌肉萎缩，也称为肌病或肌肉萎缩，是一种虚弱和危及生命的疾病。肌病是许多疾病的一种病理状态，包括癌症、糖尿病、COPD和艾滋病，是缺乏运动和衰老(骨质疏松症)的自然后果。当肌肉质量的净损失导致蛋白质合成和蛋白质降解之间的平衡改变时，就会发生肌肉萎缩。泛素途径和特定的泛素途径酶直接与萎缩的进展有关。泛素E3连接酶肌肉特异性环指E3连接酶(MuRF1)上调，在许多肌肉萎缩模型中增加蛋白质降解和肌肉萎缩。MuRF1的抑制可能是一种防止或逆转与多种病理相关的肌肉萎缩的新机制。我们筛选了一个抑制MuRF1活性的小分子文库，并鉴定了一个抑制MuRF1活性的抑制剂P013222。此外，P013222被证明抑制MuRF1依赖的底物泛素化，并在细胞萎缩模型中有效地抑制MuRF1。因此，MuRF1可以以一种特定的方式作为靶点，并在细胞萎缩模型中产生积极的结果。
Progressive muscle wasting, also known as myopathy or muscle atrophy is a debilitating and life-threatening disorder. Myopathy is a pathological condition of many diseases including cancer, diabetes, COPD, and AIDS and is a natural consequence of inactivity and aging (sarcopenia). Muscle atrophy occurs when there is a net loss of muscle mass resulting in a change in the balance between protein synthesis and protein degradation. The ubiquitin pathway and specific ubiquitin pathway enzymes have been directly implicated in the progression of atrophy. The ubiquitin E3 ligase Muscle-specific RING Finger E3 ligase (MuRF1) is upregulated and increases protein degradation and muscle wasting in numerous muscle atrophy models. The inhibition of MuRF1 could be a novel mechanism to prevent or reverse muscle wasting associated with various pathologies. We screened a small molecule library for inhibitors to MuRF1 activity and identified P013222, an inhibitor of MuRF1 autoubiquitylation. Further, P013222 was shown to inhibit MuRF1-dependent substrate ubiquitylation, and was active in inhibiting MuRF1 in a cellular atrophy model. Thus MuRF1 can be targeted in a specific manner and produce positive results in cellular atrophy models.