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.
Highlights
The skeletal muscle stem cells (MuSCs, satellite cells) are the stem cells located under the basal layer of mature muscle fibers and are necessary for normal muscle growth and regeneration
In order to study the function of METTL3 in muscle stem cells and muscle regeneration, we established a genetic mouse model of conditional ablation of METTL3 in adult skeletal muscle stem cells
After induction of METTL3 knockout in the muscle stem cells with tamoxifen (Figure 1(a)), the muscle regeneration was induced by injecting cardiotoxin (CTX) into the tibialis anterior (TA) muscles of METTL3 cKO mice and the control mice, and the muscle samples were collected at different timepoints after injection
Summary
The skeletal muscle stem cells (MuSCs, satellite cells) are the stem cells located under the basal layer of mature muscle fibers and are necessary for normal muscle growth and regeneration. The Pax7+ MuSCs become activated and proliferate as progenitor cell myoblasts, which differentiate into myotubes and further mature as functional muscles. The process of MuSC differentiation and fusion is mediated by several transcription factors termed the myogenic regulatory factors (MRFs) including myoblast determination protein (MyoD), myosin, and myogenin (Myog) [3]. The m6A modification requires a defined set of “writer” proteins including the active methyltransferase METTL3 and its cofactor METTL14, to deposit the methyl groups on mRNAs [9, 10]. Different reader proteins including the YTHDF, YTHDC, and IGFBP family proteins recognize the m6A modifications on mRNAs and facilitate the stability, processing, transport, and translation of mRNAs. Stem Cells International the m6A modification plays important functions in posttranscriptional gene expression regulation
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