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bioRxiv · 10.1101/2024.04.01.587665

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

Prola, A.·Dupont, O.·Rajendran, J.·Chabry, F.·Koenig, S.·Frieden, M.·Castets, P.
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Abstract

Neuromuscular junction (NMJ) instability is central in muscle dysfunction occurring in neuromuscular disorders and aging. NMJ maintenance requires regionalized regulation of synaptic genes, previously associated with Ca2+-dependent pathways. However, what sustains Ca2+ micro-domains in myofibers and allows a rapid response to denervation is not known. Here, we identify that Store-Operated Calcium Entry (SOCE) plays a critical role in synaptic gene regulation. SOCE components show differential enrichment in sub- and non-synaptic muscle regions. Especially, STIM1 accumulation at rough endoplasmic reticulum associates with functional SOCE at the endplate. Denervation increases SOCE in non- and sub-synaptic regions, together with reticulum remodeling. Stim1 knockdown hampers denervation-induced synaptic gene up-regulation, while STIM1 overexpression increases synaptic gene expression in innervated muscle. Finally, mTORC1 activation mimics the effect of denervation on SOCE capacity, STIM1 localization and reticulum remodeling. Together, our results reveal a decisive role of SOCE in sensing innervation and regulating muscle response to denervation. They further suggest that SOCE perturbation may contribute to neuromuscular integrity loss in pathological conditions associated with mTORC1 dysregulation.

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Prola, A., Dupont, O., Rajendran, J., Chabry, F., Koenig, S., Frieden, M., Castets, P.. 2024-04-02. mTORC1-dependent SOCE activity regulates synaptic gene expression and muscle response to denervation. https://doi.org/10.1101/2024.04.01.587665

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