Effect of AAV-mediated overexpression of ATF5 and downstream targets of an integrated stress response in murine skeletal muscle.
Effect of AAV-mediated overexpression of ATF5 and downstream targets of an integrated stress response in murine skeletal muscle.
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DOI：
10.1038/s41598-021-99432-4
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发表时间：
2021-10-05
影响因子：
4.6
通讯作者：
Brameld JM
中科院分区：
文献类型：
--
作者：
Brearley-Sholto MC;Loczenski-Brown DM;Jones S;Daniel ZCTR;Ebling FJP;Parr T;Brameld JM
我们以前报道过，生长启动子诱导的骨骼肌肥大协同上调了与整合应激反应(ISR)相关的基因的表达，以及潜在的ISR调节因子。因此，我们使用腺相关病毒(AAV)介导的这些基因在小鼠骨骼肌中单独或联合过表达，以测试它们是否诱导肌肉肥大。将各靶基因的AAV注射入小鼠胫骨前肌(TA)，28d后测定其对骨骼肌生长的影响。单独地，精氨酸酶-2(Arg2)和激活转录因子-5(Atf5)的AAV构建减少了后肢肌肉重量，并上调了与ISR相关的基因的表达。AAV-Atf5还降低了肌球蛋白重链(MyHC)-IIb的mRNA，但增加了MyHC-IIA和异柠檬酸脱氢酶-2(IDH2)的mRNA，提示ATF5是IDH2的一种新的转录调控因子。AAV-Atf5减小了TA氧化纤维和糖酵解纤维的尺寸，而不影响纤维类型的比例，而Atf5与CEBPG(CCAAT增强子结合蛋白-γ)联合使用仅减小了糖酵解纤维的尺寸，并倾向于增加氧化纤维的比例。持续的Atf5过表达可能维持ISR的激活，从而减少蛋白质合成和/或增加蛋白质降解和可能的细胞凋亡，导致肌肉生长抑制，而Arg2的过表达具有类似的作用。
We previously reported that growth promoter-induced skeletal muscle hypertrophy co-ordinately upregulated expression of genes associated with an integrated stress response (ISR), as well as potential ISR regulators. We therefore used Adeno-Associated Virus (AAV)-mediated overexpression of these genes, individually or in combination, in mouse skeletal muscle to test whether they induced muscle hypertrophy. AAV of each target gene was injected into mouse Tibialis anterior (TA) and effects on skeletal muscle growth determined 28 days later. Individually, AAV constructs for Arginase-2 (Arg2) and Activating transcription factor-5 (Atf5) reduced hindlimb muscle weights and upregulated expression of genes associated with an ISR. AAV-Atf5 also decreased Myosin heavy chain (MyHC)-IIB mRNA, but increased MyHC-IIA and isocitrate dehydrogenase-2 (Idh2) mRNA, suggesting ATF5 is a novel transcriptional regulator of Idh2. AAV-Atf5 reduced the size of both TA oxidative and glycolytic fibres, without affecting fibre-type proportions, whereas Atf5 combined with Cebpg (CCAAT enhancer binding protein-gamma) only reduced the size of glycolytic fibres and tended to increase the proportion of oxidative fibres. It is likely that persistent Atf5 overexpression maintains activation of the ISR, thereby reducing protein synthesis and/or increasing protein degradation and possibly apoptosis, resulting in inhibition of muscle growth, with overexpression of Arg2 having a similar effect.
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影响因子：
4.6
作者：
Sepulveda PV;Lamon S;Hagg A;Thomson RE;Winbanks CE;Qian H;Bruce CR;Russell AP;Gregorevic P
通讯作者：
Gregorevic P
影响因子：
3.7
作者：
Gannon PO;Godin-Ethier J;Hassler M;Delvoye N;Aversa M;Poisson AO;Péant B;Alam Fahmy M;Saad F;Lapointe R;Mes-Masson AM
通讯作者：
Mes-Masson AM
DOI：
10.1083/jcb.201702058
发表时间：
2017-07-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Quirós PM;Prado MA;Zamboni N;D'Amico D;Williams RW;Finley D;Gygi SP;Auwerx J
通讯作者：
Auwerx J
影响因子：
5.4
作者：
Trichas, Georgios;Begbie, Jo;Srinivas, Shankar
通讯作者：
Srinivas, Shankar
GADD45蛋白质：与衰老，寿命和与年龄相关的病理相关。
影响因子：
13.1
作者：
Moskalev, Alexey A.;Smit-McBride, Zeljka;Shaposhnikov, Mikhail V.;Plyusnina, Ekaterina N.;Zhavoronkov, Alex;Budovsky, Arie;Tacutu, Robi;Fraifeld, Vadim E.
通讯作者：
Fraifeld, Vadim E.