Ubiquitin E3 ligase Atrogin-1 protein is regulated via the rapamycin-sensitive mTOR-S6K1 signaling pathway in C2C12 muscle cells

被引:14
作者
Nishimura, Yusuke [1 ]
Chunthorng-Orn, Jitpisute [1 ]
Lord, Samuel [1 ]
Musa, Ibrahim [1 ]
Dawson, Peter [1 ,2 ]
Holm, Lars [1 ]
Lai, Yu-Chiang [1 ,2 ,3 ]
机构
[1] Univ Birmingham, Sch Sport Exercise & Rehabil Sci, Birmingham, W Midlands, England
[2] Univ Birmingham, MRC, Versus Arthrit Ctr Musculoskeletal Ageing Res, Birmingham, W Midlands, England
[3] Univ Birmingham, Inst Metab & Syst Res, Birmingham, W Midlands, England
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2022年 / 323卷 / 01期
基金
英国生物技术与生命科学研究理事会;
关键词
mTORC1; skeletal muscle; ubiquitin proteasome system; SKELETAL-MUSCLE; S6; KINASE; ATROPHY; EXPRESSION; GROWTH; PHOSPHORYLATION; RESISTANCE; HYPERTROPHY; DEGRADATION; METABOLISM;
D O I
10.1152/ajpcell.00384.2021
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Atrogin-1 and Muscle-specific RING finger protein 1 (MuRF1) are highly expressed in multiple conditions of skeletal muscle atro-phy. The phosphoinositide 3-kinase (PI3K)/Akt/forkhead box (FoxO) signaling pathway is well known to regulate Atrogin-1 and MuRF1 gene expressions. However, Akt activation also activates the mechanistic target of rapamycin complex 1 (mTORC1), which induces skeletal muscle hypertrophy. Whether mTORC1-dependent signaling has a role in regulating Atrogin-1 and/or MuRF1 gene and protein expression is currently unclear. In this study, we showed that activation of insulin-mediated Akt signaling sup-presses both Atrogin-1 and MuRF1 protein contents and that inhibition of Akt increases both Atrogin-1 and MuRF1 protein con-tents in C2C12 myotubes. Interestingly, inhibition of mTORC1 with a specific mTORC1 inhibitor, rapamycin, increased Atrogin-1, but not MuRF1, protein content. Furthermore, activation of AMP-activated protein kinase (AMPK), a negative regulator of the mTORC1 signaling pathway, also showed distinct time-dependent changes between Atrogin-1 and MuRF1 protein contents, sug-gesting differential regulatory mechanisms between Atrogin-1 and MuRF1 protein content. To further explore the downstream of mTORC1 signaling, we employed a specific S6K1 inhibitor, PF-4708671. We found that Atrogin-1 protein content was dose -dependently increased with PF-4708671 treatment, whereas MuRF1 protein content was decreased at 50 mu M of PF-4708671 treatment. However, MuRF1 protein content was unexpectedly increased by PF-4708671 treatment for a longer period. Overall, our results indicate that Atrogin-1 and MuRF1 protein contents are regulated by different mechanisms, the downstream of Akt, and that Atrogin-1 protein content can be regulated by the rapamycin-sensitive mTOR-S6K1-dependent signaling pathway.
引用
收藏
页码:C215 / C225
页数:11
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