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Aim: Type 2 diabetes mellitus (T2DM) is one of the most common diseases, and epigenetic modification N6-methyladenosine (m(6)A) is essential for transcriptional modulation involved in its development. However, the precise role and landscape of transcriptome-wide m(6)A alterations in molecular adaptations after physical exercise have yet to be fully elucidated. Methods: Four-week-old male C57BL/6J mice received a high-fat diet (HFD) for 12 weeks to establish a diabetic state, and HFD mice were simultaneously subjected to physical exercise (HFD + EX). The hepatic RNA m(6)A methylome was examined, the conjoint MeRIP-seq and RNA-seq was performed, and the exercise-modulated genes were confirmed. Results: Physical exercise significantly ameliorates liver metabolic disorder and triggers a dynamic change in hepatic RNA m(6)A. By analyzing the distribution of m(6)A in transcriptomes, an abundance of m(6)A throughout mRNA transcripts and a pattern of conserved m(6)A after physical exercise was identified. It is noteworthy that conjoint MeRIP-seq and RNA-seq data revealed that both differentially methylated genes and differentially expressed genes were enriched in all stages of the PI3K-Akt signaling pathway, in particular the upstream nodes of this pathway, which are considered a valuable therapeutic target for T2DM. Moreover, in vivo and in vitro analyses showed that exercise-mediated methyltransferase Rbm15 positively regulated the expression of two upstream genes (Itga3 and Fgf21) in an m(6)A-dependent manner. Conclusion: These findings highlight the pivotal role of the exercise-induced m(6)A epigenetic network and contribute insights into the intricate epigenetic mechanism underlying insulin signaling.
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ACTA PHYSIOLOGICA
ISSN: 1748-1708
Year: 2024
Issue: 6
Volume: 240
5 . 6 0 0
JCR@2023
Cited Count:
WoS CC Cited Count: 2
SCOPUS Cited Count: 1
ESI Highly Cited Papers on the List: 0 Unfold All
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30 Days PV: 0
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