A novel mitochondrial micropeptide MPM enhances mitochondrial respiratory activity and promotes myogenic differentiation
A novel mitochondrial micropeptide MPM enhances mitochondrial respiratory activity and promotes myogenic differentiation
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新型线粒体微肽 MPM 增强线粒体呼吸活性并促进肌原性分化
DOI：
10.1038/s41419-019-1767-y
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发表时间：
2019-07-11
影响因子：
9
通讯作者：
Zhuang, Shi-Mei
中科院分区：
文献类型：
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作者：
Lin, Yi-Fang;Xiao, Man-Huan;Zhuang, Shi-Mei
微肽属于一类新发现的长度为100个氨基酸的小分子，其功能在很大程度上仍然未知。在这里，我们发现了一种新的肌肉富集肽，定位于线粒体(命名为MPM，线粒体中的微肽)，并在C2C12成肌细胞的体外分化和体内出生后早期骨骼肌发育以及心脏毒素(CTX)损伤后的肌肉再生过程中上调。在胫骨肌营养不良症和Duchenne肌营养不良症患者的肌肉组织中发现MPM表达下调。此外，MPM的沉默抑制了C2C12成肌细胞向肌管的分化，而MPM的过度表达则促进了它的分化。−/−小鼠的骨骼肌纤维较小，肌肉运动能力较差，如四肢最大握力下降、从轮杆上掉下的潜伏期和力竭游泳时间。与野生型小鼠相比，注射环磷酰胺后Pax7、MyoD和MyoG的表达降低，再生的肌纤维变小，MPM−/−小鼠的肌肉再生也受到损害。基于功能获得和丧失的机制研究表明，MPM增加了线粒体的耗氧量和ATP的产生。此外，异位表达能促进线粒体呼吸的pGC-1α，减弱了siMPM对成肌分化的抑制作用。这些结果表明，MPM可能通过增强线粒体的呼吸活性来促进肌源性分化和肌纤维生长，这突显了微肽在肌肉发生和线粒体活动的复杂调控网络中的重要性，并暗示MPM可能成为肌营养不良治疗的潜在靶点。
Micropeptides belong to a class of newly identified small molecules with <100 amino acids in length, and their functions remain largely unknown. Here, we identified a novel muscle-enriched micropeptide that was localized to mitochondria (named MPM,micropeptide inmitochondria) and upregulated during in vitro differentiation of C2C12 myoblasts and in vivo early postnatal skeletal muscle development, and muscle regeneration after cardiotoxin (CTX) damage. Downregulation of MPM was observed in the muscular tissues of tibial muscular dystrophy and Duchenne muscular dystrophy patients. Furthermore, MPM silencing inhibited the differentiation of C2C12 myoblasts into myotubes, whereas MPM overexpression stimulated it. MPM−/−mice exhibited smaller skeletal muscle fibers and worse muscle performance, such as decrease in the maximum grip force of limbs, the latency to fall off rotarod, and the exhausting swimming time. Muscle regeneration was also impaired in MPM−/−mice, as evidenced by lower expression of Pax7, MyoD, and MyoG after CTX injection and smaller regenerated myofibers, compared with wild-type mice. Mechanistical investigations based on both gain- and loss-of function studies revealed that MPM increased oxygen consumption and ATP production of mitochondria. Moreover, ectopic expression of PGC-1α, which can enhance mitochondrial respiration, attenuated the inhibitory effect of siMPM on myogenic differentiation. These results imply that MPM may promote myogenic differentiation and muscle fiber growth by enhancing mitochondrial respiratory activity, which highlights the importance of micropeptides in the elaborate regulatory network of both myogenesis and mitochondrial activity and implicates MPM as a potential target for muscular dystrophy therapy.