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Muscle 4EBP1 activation modifies the structure and function of the neuromuscular junction in mice

Author

Listed:
  • Seok-Ting J. Ang

    (National University of Singapore
    National University of Singapore)

  • Elisa M. Crombie

    (National University of Singapore)

  • Han Dong

    (National University of Singapore)

  • Kuan-Ting Tan

    (National University of Singapore)

  • Adriel Hernando

    (National University of Singapore)

  • Dejie Yu

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Stuart Adamson

    (Buck Institute for Research on Aging)

  • Seonyoung Kim

    (National University of Singapore)

  • Dominic J. Withers

    (Medical Research Council Clinical Council London Institute of Medical Sciences (LMS)
    Imperial College London)

  • Hua Huang

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Shih-Yin Tsai

    (National University of Singapore
    National University of Singapore)

Abstract

Dysregulation of mTOR complex 1 (mTORC1) activity drives neuromuscular junction (NMJ) structural instability during aging; however, downstream targets mediating this effect have not been elucidated. Here, we investigate the roles of two mTORC1 phosphorylation targets for mRNA translation, ribosome protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), in regulating NMJ structural instability induced by aging and sustained mTORC1 activation. While myofiber-specific deletion of S6k1 has no effect on NMJ structural integrity, 4EBP1 activation in murine muscle induces drastic morphological remodeling of the NMJ with enhancement of synaptic transmission. Mechanistically, structural modification of the NMJ is attributed to increased satellite cell activation and enhanced post-synaptic acetylcholine receptor (AChR) turnover upon 4EBP1 activation. Considering that loss of post-synaptic myonuclei and reduced NMJ turnover are features of aging, targeting 4EBP1 activation could induce NMJ renewal by expanding the pool of post-synaptic myonuclei as an alternative intervention to mitigate sarcopenia.

Suggested Citation

  • Seok-Ting J. Ang & Elisa M. Crombie & Han Dong & Kuan-Ting Tan & Adriel Hernando & Dejie Yu & Stuart Adamson & Seonyoung Kim & Dominic J. Withers & Hua Huang & Shih-Yin Tsai, 2022. "Muscle 4EBP1 activation modifies the structure and function of the neuromuscular junction in mice," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35547-0
    DOI: 10.1038/s41467-022-35547-0
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    References listed on IDEAS

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    1. Perrine Castets & Nathalie Rion & Marine Théodore & Denis Falcetta & Shuo Lin & Markus Reischl & Franziska Wild & Laurent Guérard & Christopher Eickhorst & Marielle Brockhoff & Maitea Guridi & Chikwen, 2019. "mTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    2. Daniel J. Ham & Anastasiya Börsch & Shuo Lin & Marco Thürkauf & Martin Weihrauch & Judith R. Reinhard & Julien Delezie & Fabienne Battilana & Xueyong Wang & Marco S. Kaiser & Maitea Guridi & Michael S, 2020. "The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia," Nature Communications, Nature, vol. 11(1), pages 1-21, December.
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