Nontranslational function of leucyl-tRNA synthetase regulates myogenic differentiation and skeletal muscle regeneration

Kook Son, Jae Sung You, Mee Sup Yoon, Chong Dai, Jong Hyun Kim, Nidhi Khanna, Aditi Banerjee, Susan A. Martinis, Gyoonhee Han, Jung Min Han, Sunghoon Kim, Jie Chen

Research output: Contribution to journalArticle

Abstract

Aside from its catalytic function in protein synthesis, leucyl-tRNA synthetase (LRS) has a nontranslational function in regulating cell growth via the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathway by sensing amino acid availability. mTOR also regulates skeletal myogenesis, but the signaling mechanism is distinct from that in cell growth regulation. A role of LRS in myogenesis has not been reported. Here we report that LRS negatively regulated myoblast differentiation in vitro. This function of LRS was independent of its regulation of protein synthesis, and it required leucine-binding but not tRNA charging activity of LRS. Local knock down of LRS accelerated muscle regeneration in a mouse injury model, and so did the knock down of Rag or Raptor. Further in vitro studies established a Rag-mTORC1 pathway, which inhibits the IRS1-PI3K-Akt pathway, to be the mediator of the nontranslational function of LRS in myogenesis. BC-LI-0186, an inhibitor reported to disrupt LRS-Rag interaction, promoted robust muscle regeneration with enhanced functional recovery, and this effect was abolished by cotreatment with an Akt inhibitor. Taken together, our findings revealed what we believe is a novel function for LRS in controlling the homeostasis of myogenesis, and suggested a potential therapeutic strategy to target a noncanonical function of a housekeeping protein.

Original languageEnglish (US)
Pages (from-to)2088-2093
Number of pages6
JournalJournal of Clinical Investigation
Volume129
Issue number5
DOIs
StatePublished - May 1 2019

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Nontranslational function of leucyl-tRNA synthetase regulates myogenic differentiation and skeletal muscle regeneration'. Together they form a unique fingerprint.

  • Cite this