Reduced Dnmt3a increases Gdf5 expression with suppressed satellite cell differentiation and impaired skeletal muscle regeneration

Yukino Hatazawa, Yusuke Ono, Yuma Hirose, Sayaka Kanai, Nobuharu L. Fujii, Shuichi Machida, Ichizo Nishino, Takahiko Shimizu, Masaki Okano, Yasutomi Kamei, Yoshihiro Ogawa

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

DNAmethylation is an epigenetic mechanism regulating gene expression. In this study, we observed that DNAmethyltransferase 3a (Dnmt3a) expression is decreased after muscle atrophy.Wemade skeletalmuscle-specific Dnmt3a-knockout (Dnmt3a-KO) mice. The regeneration capacity after muscle injury was markedly decreased in Dnmt3a-KOmice.DiminishedmRNAand protein expression of Dnmt3awere observed in skeletalmuscles aswell as in satellite cells, which are important formuscle regeneration, in Dnmt3a-KOmice. Dnmt3a-KO satellite cell showed smaller in size (length/area), suggesting suppressed myotube differentiation. Microarray analysis of satellite cells showed that expression of growth differentiation factor 5 (Gdf5)mRNAwasmarkedly increased in Dnmt3a-KOmice. TheDNA methylation level of the Gdf5 promoter wasmarkedly decreased in Dnmt3a-KO satellite cells. In addition, DNA methylation inhibitor azacytidine treatment increased Gdf5 expression in wild-type satellite cells, suggesting Gdf5 expression is regulated byDNAmethylation. Also, we observed increased inhibitor of differentiation (a target of Gdf5)mRNA expression in Dnmt3a-KO satellite cells. Thus, Dnmt3a appears to regulate satellite cell differentiation viaDNAmethylation. Thismechanism may play a role in the decreased regeneration capacity during atrophy such as in aged sarcopenia.

Original languageEnglish
Pages (from-to)1452-1467
Number of pages16
JournalFASEB Journal
Volume32
Issue number3
DOIs
Publication statusPublished - Mar 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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