Self-transducible LRS-UNE-L peptide enhances muscle regeneration
DC Field | Value | Language |
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dc.contributor.author | Baek, Mi-Ock | - |
dc.contributor.author | Cho, Hye-Jeong | - |
dc.contributor.author | Min, Do Sik | - |
dc.contributor.author | Choi, Cheol Soo | - |
dc.contributor.author | Yoon, Mee-Sup | - |
dc.date.accessioned | 2022-04-09T03:40:04Z | - |
dc.date.available | 2022-04-09T03:40:04Z | - |
dc.date.created | 2022-02-25 | - |
dc.date.issued | 2022-04 | - |
dc.identifier.issn | 2190-5991 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/83912 | - |
dc.description.abstract | Background: Muscle regeneration includes proliferation and differentiation of muscle satellite cells, which involves the mammalian target of rapamycin (mTOR). We identified the C-terminal unique attached sequence motif (UNE) domain of leucyl-tRNA synthetase (LRS-UNE-L) as an mTORC1 (mTOR complex1)-activating domain that acts through Vps34 and phospholipase D1 (PLD1) when introduced in the form of a muscle-enhancing peptide. Methods: In vitro Vps34 lipid kinase assay, phosphatidylinositol 3-phosphate (PI(3)P) measurement, in vivo PLD1 assay, and western blot assay were performed in HEK293 cells to test the effect of the LRS-UNE-L on the Vps34-PLD1-mTOR pathway. Adeno-associated virus (AAV)-LRS-UNE-L was transduced in C2C12 cells in vitro, in BaCl2-injured tibialis anterior (TA) muscles, and in 18-month-old TA muscles to analyse its effect on myogenesis, muscle regeneration, and aged muscle, respectively. The muscle-specific cell-permeable peptide M12 was fused with LRS-UNE-L and tested for cell integration in C2C12 and HEK293 cells using FACS analysis and immunocytochemistry. Finally, M12-LRS-UNE-L was introduced into BaCl2-injured TA muscles of 15-week-old Pld1+/+ or Pld1−/− mice, and its effect was analysed by measurement of cross-sectional area of regenerating muscle fibres. Results: The LRS-UNE-L expression restored amino acid-induced S6K1 phosphorylation in LRS knockdown cells in a RagD GTPases-independent manner (421%, P = 0.007 vs. LRS knockdown control cells). The LRS-UNE-L domain was directly bound to Vps34; this interaction was accompanied by increases in Vps34 activity (166%, P = 0.0352), PI(3)P levels (146%, P = 0.0039), and PLD1 activity (228%, P = 0.0294) compared with amino acid-treated control cells, but it did not affect autophagic flux. AAV-delivered LRS-UNE-L domain augmented S6K1 phosphorylation (174%, P = 0.0013), mRNA levels of myosin heavy chain (MHC) (122%, P = 0.0282) and insulin-like growth factor 2 (IGF2) (146%, P = 0.008), and myogenic fusion (133%, P = 0.0479) in C2C12 myotubes. AAV-LRS-UNE-L increased the size of regenerating muscle fibres in BaCl2-injured TA muscles (124%, P = 0.0279) (n = 9–10), but it did not change the muscle fibre size of TA muscles in old mice. M12-LRS-UNE-L was preferentially delivered into C2C12 cells compared with HEK293 cells and augmented regeneration of BaCl2-injured TA muscles in a PLD1-dependent manner (116%, P = 0.0022) (n = 6). Conclusions: Our results provide compelling evidence that M12-LRS-UNE-L could be a muscle-enhancing protein targeting mTOR. © 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | WILEY | - |
dc.relation.isPartOf | Journal of Cachexia, Sarcopenia and Muscle | - |
dc.title | Self-transducible LRS-UNE-L peptide enhances muscle regeneration | - |
dc.type | Article | - |
dc.type.rims | ART | - |
dc.description.journalClass | 1 | - |
dc.identifier.wosid | 000757229900001 | - |
dc.identifier.doi | 10.1002/jcsm.12947 | - |
dc.identifier.bibliographicCitation | Journal of Cachexia, Sarcopenia and Muscle, v.13, no.2, pp.1277 - 1288 | - |
dc.description.isOpenAccess | N | - |
dc.identifier.scopusid | 2-s2.0-85124715241 | - |
dc.citation.endPage | 1288 | - |
dc.citation.startPage | 1277 | - |
dc.citation.title | Journal of Cachexia, Sarcopenia and Muscle | - |
dc.citation.volume | 13 | - |
dc.citation.number | 2 | - |
dc.contributor.affiliatedAuthor | Baek, Mi-Ock | - |
dc.contributor.affiliatedAuthor | Cho, Hye-Jeong | - |
dc.contributor.affiliatedAuthor | Choi, Cheol Soo | - |
dc.contributor.affiliatedAuthor | Yoon, Mee-Sup | - |
dc.type.docType | Article; Early Access | - |
dc.subject.keywordAuthor | M12-LRS-UNE-L | - |
dc.subject.keywordAuthor | mTOR | - |
dc.subject.keywordAuthor | Muscle differentiation | - |
dc.subject.keywordAuthor | Muscle regeneration | - |
dc.subject.keywordAuthor | Muscle-enhancing protein | - |
dc.subject.keywordAuthor | Self-transducible peptide | - |
dc.subject.keywordPlus | TRANSFER-RNA SYNTHETASE | - |
dc.subject.keywordPlus | MAMMALIAN TARGET | - |
dc.subject.keywordPlus | MTORC1 | - |
dc.subject.keywordPlus | ATROPHY | - |
dc.relation.journalResearchArea | Geriatrics & Gerontology | - |
dc.relation.journalResearchArea | General & Internal Medicine | - |
dc.relation.journalWebOfScienceCategory | Geriatrics & Gerontology | - |
dc.relation.journalWebOfScienceCategory | Medicine, General & Internal | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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