Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA.
Institute of Medicinal Plant Development, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
FASEB J. 2019 Aug;33(8):9672-9684. doi: 10.1096/fj.201900582R. Epub 2019 Jun 4.
Skeletal muscles contain heterogeneous myofibers that are different in size and contractile speed, with type IIb myofiber being the largest and fastest. Here, we identify methyltransferase-like 21e (Mettl21e), a member of newly classified nonhistone methyltransferases, as a gene enriched in type IIb myofibers. The expression of was strikingly up-regulated in hypertrophic muscles and during myogenic differentiation and . Knockdown (KD) of led to atrophy of cultured myotubes, and targeted mutation of in mice reduced the size of IIb myofibers without affecting the composition of myofiber types. Mass spectrometry and methyltransferase assay revealed that Mettl21e methylated valosin-containing protein (Vcp/p97), a key component of the ubiquitin-proteasome system. KD or knockout of Mettl21e resulted in elevated 26S proteasome activity, and inhibition of proteasome activity prevented atrophy of KD myotubes. These results demonstrate that Mettl21e functions to maintain myofiber size through inhibiting proteasome-mediated protein degradation.-Wang, C., Zhang, B., Ratliff, A. C., Arrington, J., Chen, J., Xiong, Y., Yue, F., Nie, Y., Hu, K., Jin, W., Tao, W. A., Hrycyna, C. A., Sun, X., Kuang, S. Methyltransferase-like 21e inhibits 26S proteasome activity to facilitate hypertrophy of type IIb myofibers.
骨骼肌包含大小和收缩速度不同的异质性肌纤维，其中 IIb 型肌纤维最大且收缩速度最快。在这里，我们鉴定出甲基转移酶样蛋白 21e（Mettl21e），它是新分类的非组蛋白甲基转移酶家族的一员，作为在 IIb 型肌纤维中富集的基因。在肥大肌肉和肌生成分化过程中，的表达显著上调。敲低（KD）导致培养的肌管萎缩，而在小鼠中靶向突变导致 IIb 型肌纤维变小而不影响肌纤维类型的组成。质谱和甲基转移酶测定显示 Mettl21e 甲基化泛素结合酶 p97（Vcp/p97），这是泛素蛋白酶体系统的关键成分。KD 或 Mettl21e 的敲除导致 26S 蛋白酶体活性升高，而蛋白酶体抑制剂可防止 KD 肌管萎缩。这些结果表明 Mettl21e 通过抑制蛋白酶体介导的蛋白质降解来维持肌纤维大小。-Wang, C., Zhang, B., Ratliff, A. C., Arrington, J., Chen, J., Xiong, Y., Yue, F., Nie, Y., Hu, K., Jin, W., Tao, W. A., Hrycyna, C. A., Sun, X., Kuang, S. Methyltransferase-like 21e inhibits 26S proteasome activity to facilitate hypertrophy of type IIb myofibers.
