Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice.
Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice.
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DOI：
10.1038/s41598-017-14290-3
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发表时间：
2017-10-27
影响因子：
4.6
通讯作者：
Bates GP
中科院分区：
文献类型：
--
作者：
Bondulich MK;Jolinon N;Osborne GF;Smith EJ;Rattray I;Neueder A;Sathasivam K;Ahmed M;Ali N;Benjamin AC;Chang X;Dick JRT;Ellis M;Franklin SA;Goodwin D;Inuabasi L;Lazell H;Lehar A;Richard-Londt A;Rosinski J;Smith DL;Wood T;Tabrizi SJ;Brandner S;Greensmith L;Howland D;Munoz-Sanjuan I;Lee SJ;Bates GP
亨廷顿舞蹈病（HD）是一种遗传性神经退行性疾病，骨骼肌萎缩是其常见特征，多种证据支持HD小鼠模型中以肌肉为基础的病理生理学。抑制肌肉生长抑制素信号会增加肌肉质量，基于此的治疗方法正在临床开发中。我们使用可溶性ActRIIB诱饵受体（ACVR2B/Fc）来测试肌肉生长抑制素/激活素a抑制在R6/2 HD小鼠模型中的作用。从5周龄到11周龄，每周给药可以预防体重减轻、骨骼肌萎缩、肌肉无力、收缩异常、EDL肌肉功能运动单位的丧失和延迟终末期疾病。抑制肌生长抑制素/激活素A信号通路激活转录谱，增加野生型和R6/2小鼠的肌肉质量，但对调节亨廷顿氏病相关的广泛转录失调作用不大，这与治疗对HTT聚集水平影响不大一致。抑制肌肉生长抑制素信号传导的方式目前正在各种适应症的临床试验中，其结果将为评估针对HD患者的这一途径的潜在益处提供机会。
Huntington’s disease (HD) is an inherited neurodegenerative disorder of which skeletal muscle atrophy is a common feature, and multiple lines of evidence support a muscle-based pathophysiology in HD mouse models. Inhibition of myostatin signaling increases muscle mass, and therapeutic approaches based on this are in clinical development. We have used a soluble ActRIIB decoy receptor (ACVR2B/Fc) to test the effects of myostatin/activin A inhibition in the R6/2 mouse model of HD. Weekly administration from 5 to 11 weeks of age prevented body weight loss, skeletal muscle atrophy, muscle weakness, contractile abnormalities, the loss of functional motor units in EDL muscles and delayed end-stage disease. Inhibition of myostatin/activin A signaling activated transcriptional profiles to increase muscle mass in wild type and R6/2 mice but did little to modulate the extensive Huntington’s disease-associated transcriptional dysregulation, consistent with treatment having little impact on HTT aggregation levels. Modalities that inhibit myostatin signaling are currently in clinical trials for a variety of indications, the outcomes of which will present the opportunity to assess the potential benefits of targeting this pathway in HD patients.
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影响因子：
3.7
作者：
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通讯作者：
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影响因子：
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Greensmith, Linda
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通讯作者：
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作者：
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通讯作者：
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