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

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.

mTORC1-dependent SOCE activity regulates synaptic gene expression and muscle response to denervation

“…Previous reports identify the mTORC1 signaling pathway as a key regulator of NMJ physiology: mTORC1 is activated in response to denervation and it drives NMJ structural instability during aging 11, 30, 49, 50 . To assess potential functional interactions between SOCE and mTORC1, we first investigated whether mTORC1 modulation affects SOCE.…”

“…While the mTORC1 pathway has been shown to play a key role in NMJ maintenance and the muscle response to denervation, downstream targets mediating this effect are not well understood 11, 30, 50, 72 . We identify that constant mTORC1 activation in TSCmKO mice results in a strong increase in SOCE capacity.…”

“…Chronic increase in SOCE-associated signaling may contribute to the defective response of TSCmKO muscle to nerve injury by blunting denervation sensing and signaling cascade induction, in contrast to STIM1 acute overexpression. Several reports have highlighted the central role of mTORC1 dysregulation in NMJ integrity loss upon aging 11, 50, 72, 78 . Importantly, changes in SOCE have also been linked to aging-associated muscle dysfunction 79, 80 .…”

Postsynaptic BMP signaling regulates myonuclear properties inDrosophilalarval muscles

“…In mammals, loss of synaptic myonuclei occurs with aging and corresponds with NMJ structural and functional defects. A recent study revealed that increasing synaptic myonuclear number by muscle activation of 4EBP1, a mRNA translation regulator, led to increased acetylcholine receptor subunit expression and neurotransmission in aged mice (Ang et al, 2022). Postsynaptic BMP signaling could also be a good target in sarcopenia, an aging-related process of muscle deterioration and other conditions that implicate NMJ activity in their initiation and/or disease progression.…”

Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy

“…The mTOR signaling pathway is well described to be involved in protein synthesis, muscle hypertrophy and growth ( Bodine et al, 2001 ; Schiaffino et al, 2021 ). However, sustained activation of mTORC1 can lead to pulmonary fibrosis ( Gui et al, 2015 ) and drive neuromuscular junction structural alterations, resulting in myofiber denervation ( Ang et al, 2022 ), muscle atrophy, loss of muscle mass ( Tang et al, 2014 , 2019 ) and late-onset myopathy by increasing the expression of the E3 ubiquitin ligases atrogin1 and MuRF1 and impairing autophagy ( Castets et al, 2013 ). Inhibition of mTORC1 by rapamycin improves muscle pathology in the fukutin-deficient mouse model of dystroglycanopathy ( Foltz et al, 2016 ) and the mdx mouse model of Duchenne muscular dystrophy ( Eghtesad et al, 2011 ).…”