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

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 and Shih-Yin Tsai ()
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Seok-Ting J. Ang: 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
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)
Hua Huang: National University of Singapore
Shih-Yin Tsai: National University of Singapore

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35547-0

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