Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits.
Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits.
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去除MuRF1增加了线状肌病模型中的肌肉质量，但没有提供功能性益处。
DOI：
10.3390/ijms23158113
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发表时间：
2022-07-23
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
线状体肌病（NM）的特征是骨骼肌无力和萎缩。对于这种使人衰弱的疾病，目前尚无治愈性治疗方法。NM是由参与细丝功能、周转和维持的蛋白质突变引起的。由NEB编码的伴肌动蛋白（nebulin）突变是最常见的病因。骨骼肌萎缩与MuRF1（一种E3连接酶）的上调密切相关，MuRF1可将蛋白质靶向蛋白酶体进行降解。在此，我们报道在基于伴肌动蛋白的NM患者（也称为NEM2）以及该疾病的小鼠模型中，MuRF1蛋白水平大幅升高。我们假设在伴有肌肉萎缩的NM动物模型中敲除MuRF1会改善肌肉缺陷。为了验证这一点，我们将MuRF1基因敲除小鼠与两种NEM2小鼠模型进行杂交，一种是典型形式，另一种是严重形式。杂交后代是可存活的，并且在3个月大的小鼠中对肌肉进行了研究。对缺乏MuRF1且患有严重NM的腓肠肌进行超微结构检查发现，空泡略有增加，但肌原纤维分数面积无显著变化。MuRF1缺乏导致NM模型中各种肌肉类型的重量增加。然而，这种肌肉大小的增加与体内或体外的力量产生增加无关。我们得出结论，在NEM2小鼠中敲除MuRF1会增加肌肉大小，但不会改善肌肉功能。
Nemaline myopathy (NM) is characterized by skeletal muscle weakness and atrophy. No curative treatments exist for this debilitating disease. NM is caused by mutations in proteins involved in thin-filament function, turnover, and maintenance. Mutations in nebulin, encoded by NEB, are the most common cause. Skeletal muscle atrophy is tightly linked to upregulation of MuRF1, an E3 ligase, that targets proteins for proteasome degradation. Here, we report a large increase in MuRF1 protein levels in both patients with nebulin-based NM, also named NEM2, and in mouse models of the disease. We hypothesized that knocking out MuRF1 in animal models of NM with muscle atrophy would ameliorate the muscle deficits. To test this, we crossed MuRF1 KO mice with two NEM2 mouse models, one with the typical form and the other with the severe form. The crosses were viable, and muscles were studied in mice at 3 months of life. Ultrastructural examination of gastrocnemius muscle lacking MuRF1 and with severe NM revealed a small increase in vacuoles, but no significant change in the myofibrillar fractional area. MuRF1 deficiency led to increased weights of various muscle types in the NM models. However, this increase in muscle size was not associated with increased in vivo or in vitro force production. We conclude that knocking out MuRF1 in NEM2 mice increases muscle size, but does not improve muscle function.
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DOI：
10.1085/jgp.202012783
发表时间：
2021-03-01
期刊：
The Journal of general physiology
影响因子：
--
作者：
Gohlke J;Tonino P;Lindqvist J;Smith JE;Granzier H
通讯作者：
Granzier H
影响因子：
19
作者：
Kleiger, Gary;Mayor, Thibault
通讯作者：
Mayor, Thibault
DOI：
10.1073/pnas.1804726115
发表时间：
2018-10-09
影响因子：
11.1
作者：
Kiss B;Lee EJ;Ma W;Li FW;Tonino P;Mijailovich SM;Irving TC;Granzier HL
通讯作者：
Granzier HL
影响因子：
13.6
作者：
Kiss B;Gohlke J;Tonino P;Hourani Z;Kolb J;Strom J;Alekhina O;Smith JE 3rd;Ottenheijm C;Gregorio C;Granzier H
通讯作者：
Granzier H
影响因子：
9.9
作者：
Colombo, Irene;Scoto, Mariacristina;Muntoni, Francesco
通讯作者：
Muntoni, Francesco