Small-molecule-mediated chemical knock-down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure
Small-molecule-mediated chemical knock-down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure
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DOI：
10.1002/jcsm.12448
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发表时间：
2019-10-01
影响因子：
8.9
通讯作者：
Labeit, Siegfried
中科院分区：
文献类型：
--
作者：
Adams, Volker;Bowen, T. Scott;Labeit, Siegfried
背景慢性心力衰竭（CHF）导致膈肌肌病，严重影响患者的生活质量和预后。在这项研究中，我们的目的是评估最近发现的MuRF 1小分子抑制剂在治疗CHF诱导的膈肌肌病和收缩功能丧失中的疗效。方法结扎小鼠冠状动脉左前降支建立心肌梗死模型。假手术动物（sham）作为对照。左前降支冠状动脉结扎后一周，将动物随机分为两组-一组喂食对照啮齿动物食物，而另一组喂食含有0.1%化合物ID#704946-最近描述的MuRF 1干扰小分子的饮食。超声心动图证实10周后发生CHF。随后对隔膜进行了功能和分子分析。结果慢性心力衰竭大鼠膈肌纤维萎缩、收缩功能障碍达20%，线粒体能量代谢相关酶活性降低（P < 0.05）。在CHF小鼠中用化合物ID#704946治疗对隔膜具有有益作用：收缩功能受到保护，而线粒体酶活性和MuRF 1和MuRF 2的上调在梗死后减弱。结论CHF小鼠模型存在膈肌纤维萎缩、收缩功能受损和线粒体酶活性降低。化合物ID#704946可能通过靶向MuRF 1/MuRF 2部分地从这种情况中拯救出来。然而，在我们研究的这个阶段，我们避免声明化合物ID#704946的特定机制和靶点，因为喂食12周后的变化性质可能很复杂，不一定是由直接的机制效应引起的。
Background Chronic heart failure (CHF) leads to diaphragm myopathy that significantly impairs quality of life and worsens prognosis. In this study, we aimed to assess the efficacy of a recently discovered small-molecule inhibitor of MuRF1 in treating CHF-induced diaphragm myopathy and loss of contractile function. Methods Myocardial infarction was induced in mice by ligation of the left anterior descending coronary artery. Sham-operated animals (sham) served as controls. One week post-left anterior descending coronary artery ligation animals were randomized into two groups-one group was fed control rodent chow, whereas the other group was fed a diet containing 0.1% of the compound ID#704946-a recently described MuRF1-interfering small molecule. Echocardiography confirmed development of CHF after 10 weeks. Functional and molecular analysis of the diaphragm was subsequently performed. Results Chronic heart failure induced diaphragm fibre atrophy and contractile dysfunction by similar to 20%, as well as decreased activity of enzymes involved in mitochondrial energy production (P < 0.05). Treatment with compound ID#704946 in CHF mice had beneficial effects on the diaphragm: contractile function was protected, while mitochondrial enzyme activity and up-regulation of the MuRF1 and MuRF2 was attenuated after infarct. Conclusions Our murine CHF model presented with diaphragm fibre atrophy, impaired contractile function, and reduced mitochondrial enzyme activities. Compound ID#704946 rescued from this partially, possibly by targeting MuRF1/MuRF2. However, at this stage of our study, we refrain to claim specific mechanism(s) and targets of compound ID#704946, because the nature of changes after 12 weeks of feeding is likely to be complex and is not necessarily caused by direct mechanistic effects.