UCHL1 regulates muscle fibers and mTORC1 activity in skeletal muscle
UCHL1 regulates muscle fibers and mTORC1 activity in skeletal muscle
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DOI：
10.1016/j.lfs.2019.116699
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发表时间：
2019-09-15
期刊：
影响因子：
6.1
通讯作者：
Li, Yifan
中科院分区：
文献类型：
--
作者：
Gao, Hongbo;Freeling, Jessica;Li, Yifan
目的：骨骼肌萎缩与许多慢性病有关。有效预防和治疗肌肉萎缩仍然是一项具有挑战性的任务，因为对维持和调节肌肉质量的机制了解不完全。本研究探讨了泛素C末端水解酶L1(UCHL1)在骨骼肌中的功能作用。主要方法：采用骨骼肌特异性基因敲除UCHL1和C2C12成肌细胞UCHL1基因敲除的小鼠。肌纤维的类型和大小通过组织或细胞染色来测量。通过其下游靶蛋白的磷酸化来评估哺乳动物雷帕霉素复合体1靶分子(MTORC1)和mTORC2的活性。关键发现：在小鼠骨骼肌中，UCHL1主要在慢收缩肌纤维中表达。骨骼肌特异性敲除UCHL1基因(SkmKO)的小鼠在慢抽动比目鱼肌中表现出较大的肌纤维，而在快抽动指长伸肌(EDL)中则没有。同时，UCHL1 skmKO增强了比目鱼肌的mTORC1活性，降低了mTORC2的活性，但不影响EDL的活性。在C2C12细胞中，与对照细胞相比，UCHL1基因敲除增加了肌管的大小，增强了mTORC1的活性，降低了mTORC2的活性。UCHL1基因敲除不改变mTOR复合体的主要蛋白质，但降低mTORC1抑制因子PRAS40的蛋白质周转率。意义：这些数据揭示了UCHL1在慢抽动骨骼肌中调节mTORC1活性和骨骼肌生长的新功能。鉴于UCHL1在失神经和脊髓性肌肉萎缩中的上调，我们的发现促进了对参与肌肉萎缩的调节因子的理解。
Aims: Skeletal muscle wasting is associated with many chronic diseases. Effective prevention and treatment of muscle wasting remain as a challenging task due to incomplete understanding of mechanisms by which muscle mass is maintained and regulated. This study investigated the functional role of Ubiquitin C-terminal hydrolase L1 (UCHL1) in skeletal muscle.Main methods: Mice with skeletal muscle specific gene knockout of UCHL1 and C2C12 myoblast cells with UCHL1 knockdown were used. Muscle fiber types and size were measured using tissue or cell staining. The mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 activities were assessed with the phosphorylation of their downstream targets.Key findings: In mouse skeletal muscle, UCHL1 was primarily expressed in slow twitch muscle fibers. Mice with skeletal muscle specific knockout (skmKO) of UCHL1 exhibited enlarged muscle fiber sizes in slow twitch soleus but not fast twitch extensor digitorum longus (EDL) muscle. Meanwhile, UCHL1 skmKO enhanced mTORC1 activity and reduced mTORC2 activity in soleus but not in EDL. Consistently, in C2C12 cells, UCHL1 knockdown increased the myotube size, enhanced mTORC1 activity, and reduced mTORC2 activities as compared with control cells. UCHL1 knockdown did not change the major proteins of mTOR complex but decreased the protein turnover of PRAS40, an inhibitory factor of mTORC1.Significance: These data revealed a novel function of UCHL1 in regulation of mTORC1 activity and skeletal muscle growth in slow twitch skeletal muscle. Given the upregulation of UCHL1 in denervation and spinal muscle atrophy, our finding advances understanding of regulators that are involved in muscle wasting.