METTL3-Mediated m6A Methylation Regulates Muscle Stem Cells and Muscle Regeneration by Notch Signaling Pathway

Abstract

The Pax7+ muscle stem cells (MuSCs) are essential for skeletal muscle homeostasis and muscle regeneration upon injury, while the molecular mechanisms underlying muscle stem cell fate determination and muscle regeneration are still not fully understood. N6-methyladenosine (m6A) RNA modification is catalyzed by METTL3 and plays important functions in posttranscriptional gene expression regulation and various biological processes. Here, we generated muscle stem cell-specific METTL3 conditional knockout mouse model and revealed that METTL3 knockout in muscle stem cells significantly inhibits the proliferation of muscle stem cells and blocks the muscle regeneration after injury. Moreover, knockin of METTL3 in muscle stem cells promotes the muscle stem cell proliferation and muscle regeneration in vivo. Mechanistically, METTL3-m6A-YTHDF1 axis regulates the mRNA translation of Notch signaling pathway. Our data demonstrated the important in vivo physiological function of METTL3-mediated m6A modification in muscle stem cells and muscle regeneration, providing molecular basis for the therapy of stem cell-related muscle diseases.

Dynamic m6A mRNA Methylation Reveals the Role of METTL3/14-m6A-MNK2-ERK Signaling Axis in Skeletal Muscle Differentiation and Regeneration

“…In particular, our study provides the comprehensive description of METTL3 and METTL14 functions during myogenesis. Interestingly, METTL3/14-MNK2 appeared to promote the early stage of MuSCs proliferation, which was consistent with the recently report that METTL3 knockout in muscle stem cells significantly inhibits the proliferation of muscle stem cells and blocks the muscle regeneration after injury and konckin of METLL3 in muscle stem cells promotes the muscle stem cell proliferation and muscle regeneration in vivo (Liang et al, 2021). However, the underlying regulation of this mechanism remains elusive.…”

Characterization of Long Non-coding RNAs Modified by m6A RNA Methylation in Skeletal Myogenesis

“…Other studies focused on the modification of mRNA by m 6 A methylation, which is involved in muscle formation, maintaining muscle homeostasis, and musculoskeletal disorders ( Zhang W. et al, 2020 ). Recent studies revealed that METTL3-mediated m 6 A methylation is essential for muscle stem cell self-renewal ( Lin et al, 2020 ), muscle regeneration ( Liang et al, 2021 ), and muscle stem cell/myoblast state transitions ( Gheller et al, 2020 ). Interestingly, myogenic potential is maintained partly by the Mettl3-mediated stabilization of processed MyoD mRNA through m 6 A modification of the 5′ untranslated regions (UTR) during proliferative phases ( Kudou et al, 2017 ), and depletion of m 6 A “eraser” FTO in myoblasts leads to impaired skeletal muscle development ( Wang et al, 2017 ).…”

Current Thoughts of Notch’s Role in Myoblast Regulation and Muscle-Associated Disease

“…Since it was identified that the active writer m 6 A modification METTL3 influences the proliferation and differentiation of satellite cells. [67], Liang et al [66] tested whether Notch was affected by the mRNA modifications and influenced myoblast proliferation. Skeletal muscle repair was inhibited in METTL3 conditional knockout with decreased proliferation (less 5-Ethynyl-2 -deoxyuridine (EdU) incorporation into replicating DNA), Pax7-positive cells, and myogenin yet increased fibrosis presence [66].…”

“…Post-transcriptional modifications. A recent study has identified a novel mechanism of Notch’s influence on proliferation [ 66 ]. N6-methyladenosine (m 6 A) modification is a post-transcriptional modification of mRNA needed for appropriate gene expression and consists of either methylating the mRNA with methyltransferase METTL3 or demethylating with demethylases FTO and ALKBH5.…”