Laboratory of Animal Fat Deposition and Muscle Development, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Shaanxi, China.
Laboratory of Animal Fat Deposition and Muscle Development, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Shaanxi, China.
Life Sci. 2022 Jun 1;298:120496. doi: 10.1016/j.lfs.2022.120496. Epub 2022 Mar 26.
Skeletal muscle development has an important impact on muscle-related diseases and domestic animal meat production. The mA RNA methylation is a common post-transcriptional modification, affecting the development and metabolism of various organs. However, the effect and regulatory mechanism of methyltransferase like 3 (METTL3) on myogenesis are still unclear. Here, we showed that the mRNA levels of METTL3 was greater in skeletal muscles including extensor digitorum longus (EDL), soleus (SOL), tibialis anterior (TA) and gastrocnemius (GAS). Moreover, METTL3 highly expressed in the early stage of myoblast proliferation at hour 0 and the late stage of myoblast differentiation at day 8, indicating it was involved in myogenesis. Interestingly, METTL3 knockdown inhibited myoblast proliferation and myogenic differentiation, whereas METTL3 overexpression promoted these processes. Mechanically, METTL3 overexpression increased the ratio of mRNA mA/A and shortened the time of P21 and P27 mRNA half level, causing the mRNAs downregulation via reducing their stability. Meanwhile, the promotion of cell proliferation by METTL3 overexpression was attenuated by YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) knockdown. Furthermore, the promotion of myogenic differentiation by METTL3 overexpression was weakened by YTHDF1 knockdown through reducing the mRNA translation of MRFs including MyHC, MyoD and MyoG. Therefore, METTL3 facilitates myoblast proliferation and myogenic differentiation. Overall, these findings suggest that METTL3/mA RNA methylation/YTHDF1/2 signaling axis is a novel strategy for the regulation of skeletal muscle development.
骨骼肌发育对与肌肉相关的疾病和家畜肉生产有重要影响。mRNA 甲基化是一种常见的转录后修饰，影响各种器官的发育和代谢。然而，甲基转移酶样 3（METTL3）对肌发生的作用及其调控机制尚不清楚。在这里，我们发现 METTL3 的 mRNA 水平在包括伸趾长肌（EDL）、比目鱼肌（SOL）、胫骨前肌（TA）和腓肠肌（GAS）在内的骨骼肌中较高。此外，METTL3 在成肌细胞增殖的早期（0 小时）和晚期（第 8 天）高度表达，表明其参与肌发生。有趣的是，METTL3 敲低抑制成肌细胞增殖和肌生成分化，而 METTL3 过表达则促进这些过程。从机制上讲，METTL3 过表达增加了 mRNA mA/A 的比值，并缩短了 P21 和 P27 mRNA 半衰期的时间，通过降低其稳定性导致 mRNAs 下调。同时，METTL3 过表达促进细胞增殖的作用被 YTH N6-甲基腺苷 RNA 结合蛋白 2（YTHDF2）敲低减弱。此外，METTL3 过表达通过降低包括 MyHC、MyoD 和 MyoG 在内的 MRFs 的 mRNA 翻译，减弱了 YTHDF1 敲低对肌生成分化的促进作用。因此，METTL3 促进成肌细胞增殖和肌生成分化。总体而言，这些发现表明 METTL3/mA RNA 甲基化/YTHDF1/2 信号轴是调节骨骼肌发育的一种新策略。
