Dyrk1b promotes autophagy during skeletal muscle differentiation by upregulating 4e-bp1.
Dyrk1b promotes autophagy during skeletal muscle differentiation by upregulating 4e-bp1.
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DOI：
10.1016/j.cellsig.2021.110186
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发表时间：
2022-03
影响因子：
4.8
通讯作者：
Mani A
中科院分区：
文献类型：
--
作者：
Bhat N;Narayanan A;Fathzadeh M;Shah K;Dianatpour M;Abou Ziki MD;Mani A
Dyrk 1b基因是骨骼肌分化的关键调节因子，其功能突变的罕见获得与人类肌肉减少性肥胖（SO）和代谢综合征（MetS）相关。到目前为止，Dyrk 1b在肌纤维分化过程中调控的全球基因网络仍然难以捉摸。在这里，我们进行了非靶向蛋白质组学，以确定Dyrk 1b依赖的基因网络在分化的C2 C12肌纤维。该分析导致鉴定翻译抑制剂4 e-bp 1作为C2 C12细胞中Dyrk 1b的转录后靶点。因此，CRISPR/Cas9介导的斑马鱼中Dyrk 1b的敲除将4 e-bp 1鉴定为体内Dyrk 1b的下游靶标。Dyrk 1b基因敲除斑马鱼胚胎在发育不良的肌节中肌球蛋白重链1的表达显着降低，并且是胚胎致死的。在C2 C12细胞中使用敲低和过表达方法，我们发现4 e-bp 1增强自噬并介导Dyrk 1b对骨骼肌分化的影响。Dyrk 1bR 102 C，人类肌肉减少性肥胖相关突变通过过度激活C2 C12细胞中的4 e-bp 1/自噬轴而损害肌肉分化。引人注目的是，Dyrk 1bR 102 C细胞中有缺陷的肌肉分化通过减少自噬通量而被拯救。Dyrk 1b-4 e-bp 1-自噬轴的鉴定为与人类骨骼肌发育和疾病相关的途径提供了重要的见解。
Rare gain of function mutations in the gene encoding Dyrk1b, a key regulator of skeletal muscle differentiation, have been associated with sarcopenic obesity (SO) and metabolic syndrome (MetS) in humans. So far, the global gene networks regulated by Dyrk1b during myofiber differentiation have remained elusive. Here, we have performed untargeted proteomics to determine Dyrk1b-dependent gene-network in differentiated C2C12 myofibers. This analysis led to identification of translational inhibitor, 4e-bp1 as a post-transcriptional target of Dyrk1b in C2C12 cells. Accordingly, CRISPR/Cas9 mediated knockout of Dyrk1b in zebrafish identified 4e-bp1 as a downstream target of Dyrk1b in-vivo. The Dyrk1b knockout zebrafish embryos exhibited markedly reduced myosin heavy chain 1 expression in poorly developed myotomes and were embryonic lethal. Using knockdown and overexpression approaches in C2C12 cells, we found that 4e-bp1 enhances autophagy and mediates the effects of Dyrk1b on skeletal muscle differentiation. Dyrk1bR102C, the human sarcopenic obesity-associated mutation impaired muscle differentiation via excessive activation of 4e-bp1/autophagy axis in C2C12 cells. Strikingly, the defective muscle differentiation in Dyrk1bR102C cells was rescued by reduction of autophagic flux. The identification of Dyrk1b-4e-bp1-autophagy axis provides significant insight into pathways that are relevant to human skeletal muscle development and disorders.
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DOI：
10.1056/nejmoa1301824
发表时间：
2014-05-15
期刊：
The New England journal of medicine
影响因子：
--
作者：
Keramati AR;Fathzadeh M;Go GW;Singh R;Choi M;Faramarzi S;Mane S;Kasaei M;Sarajzadeh-Fard K;Hwa J;Kidd KK;Babaee Bigi MA;Malekzadeh R;Hosseinian A;Babaei M;Lifton RP;Mani A
通讯作者：
Mani A
影响因子：
5.1
作者：
Charkoftaki G;Thompson DC;Golla JP;Garcia-Milian R;Lam TT;Engel J;Vasiliou V
通讯作者：
Vasiliou V
影响因子：
2.5
作者：
KIMMEL, CB;BALLARD, WW;SCHILLING, TF
通讯作者：
SCHILLING, TF
影响因子：
7.3
作者：
Hernández-Hernández JM;García-González EG;Brun CE;Rudnicki MA
通讯作者：
Rudnicki MA
DOI：
10.1111/j.1749-6632.2012.06838.x
发表时间：
2013-01-01
期刊：
YEAR IN DIABETES AND OBESITY
影响因子：
--
作者：
Gujral, Unjali P.;Pradeepa, R.;Mohan, V.
通讯作者：
Mohan, V.