Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model.
Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model.
复制标题
DOI：
10.1038/s41467-017-00730-1
复制
发表时间：
2017-09-15
影响因子：
16.6
通讯作者：
Kyba M
中科院分区：
文献类型：
--
作者：
Bosnakovski D;Chan SSK;Recht OO;Hartweck LM;Gustafson CJ;Athman LL;Lowe DA;Kyba M
面肩肱型肌营养不良症是一种缓慢进展但破坏性的肌病，由转录因子DUX 4的抑制丧失引起;然而，DUX 4表达非常低，并且在患者活检中未直接检测到蛋白质。在小鼠中建立DUX 4肌病模型的努力要么过于严重，要么缺乏肌肉表型。在这里，我们表明，内源性面肩肱型肌营养不良症特异性DUX 4多聚腺苷酸化信号是令人惊讶的效率低下，并使用这一发现开发一个面肩肱型肌营养不良症小鼠模型与肌肉特异性多西环素调节DUX 4的表达。非常低的表达水平，导致罕见的DUX 4+肌核，引起缓慢进行性退行性肌病。退行性过程涉及炎症和纤维脂肪生成祖细胞室的显著扩张，导致纤维化。这些动物还表现出高频听力缺陷和损伤后骨骼肌再生受损。这种小鼠模型将有助于在体内测试的治疗，并建议参与纤维脂肪祖细胞在面肩肱型肌营养不良症。面肩肱型肌营养不良症是一种严重的肌病，由DUX 4的异常激活引起，并且不存在合适的小鼠模型。在这里，作者生成了一种具有DUX 4可滴定表达的新型小鼠模型，并表明它概括了人类病理学的几个特征。
Facioscapulohumeral muscular dystrophy is a slowly progressive but devastating myopathy caused by loss of repression of the transcription factor DUX4; however, DUX4 expression is very low, and protein has not been detected directly in patient biopsies. Efforts to model DUX4 myopathy in mice have foundered either in being too severe, or in lacking muscle phenotypes. Here we show that the endogenous facioscapulohumeral muscular dystrophy-specific DUX4 polyadenylation signal is surprisingly inefficient, and use this finding to develop an facioscapulohumeral muscular dystrophy mouse model with muscle-specific doxycycline-regulated DUX4 expression. Very low expression levels, resulting in infrequent DUX4 + myonuclei, evoke a slow progressive degenerative myopathy. The degenerative process involves inflammation and a remarkable expansion in the fibroadipogenic progenitor compartment, leading to fibrosis. These animals also show high frequency hearing deficits and impaired skeletal muscle regeneration after injury. This mouse model will facilitate in vivo testing of therapeutics, and suggests the involvement of fibroadipogenic progenitors in facioscapulohumeral muscular dystrophy. Facioscapulohumeral muscular dystrophy is a severe myopathy that is caused by abnormal activation of DUX4, and for which a suitable mouse model does not exist. Here, the authors generate a novel mouse model with titratable expression of DUX4, and show that it recapitulates several features of the human pathology.
登录
查看更多内容
影响因子：
64.8
作者：
Gabellini, D;D'Antona, G;Tupler, R
通讯作者：
Tupler, R
影响因子：
5.2
作者：
Iacovino, Michelina;Bosnakovski, Darko;Fey, Holger;Rux, Danielle;Bajwa, Gagan;Mahen, Elisabeth;Mitanoska, Ana;Xu, Zhaohui;Kyba, Michael
通讯作者：
Kyba, Michael
影响因子：
3.5
作者：
Gabriëls, J;Beckers, MC;Belayew, A
通讯作者：
Belayew, A
DOI：
10.1073/pnas.0708659104
发表时间：
2007-11-13
影响因子：
11.1
作者：
Dixit, Manjusha;Ansseau, Eugenie;Chen, Yi-Wen
通讯作者：
Chen, Yi-Wen
影响因子：
64.5
作者：
Heredia JE;Mukundan L;Chen FM;Mueller AA;Deo RC;Locksley RM;Rando TA;Chawla A
通讯作者：
Chawla A