Skeletal muscle mTORC1 regulates neuromuscular junction stability.

Martina Baraldo,Simona Boncompagni,Marcus Kruger,Marco Pirazzini,Clara Türk,Alessia Geremia,Aram Megighian,Bert Blaauw,Leonardo Nogara,Marco Sandri,Vanina Romanello,Francesca Solagna,Hendrik Nolte

doi:10.1002/jcsm.12496

Abstract

BackgroundSkeletal muscle is a plastic tissue that can adapt to different stimuli. It is well established that Mammalian Target of Rapamycin Complex 1 (mTORC1) signalling is a key modulator in mediating increases in skeletal muscle mass and function. However, the role of mTORC1 signalling in adult skeletal muscle homeostasis is still not well defined.MethodsInducible, muscle‐specific Raptor and mTOR k.o. mice were generated. Muscles at 1 and 7 months after deletion were analysed to assess muscle histology and muscle force.ResultsWe found no change in muscle size or contractile properties 1 month after deletion. Prolonging deletion of Raptor to 7 months, however, leads to a very marked phenotype characterized by weakness, muscle regeneration, mitochondrial dysfunction, and autophagy impairment. Unexpectedly, reduced mTOR signalling in muscle fibres is accompanied by the appearance of markers of fibre denervation, like the increased expression of the neural cell adhesion molecule (NCAM). Both muscle‐specific deletion of mTOR or Raptor, or the use of rapamycin, was sufficient to induce 3–8% of NCAM‐positive fibres (P < 0.01), muscle fibrillation, and neuromuscular junction (NMJ) fragmentation in 24% of examined fibres (P < 0.001). Mechanistically, reactivation of autophagy with the small peptide Tat‐beclin1 is sufficient to prevent mitochondrial dysfunction and the appearance of NCAM‐positive fibres in Raptor k.o. muscles.ConclusionsOur study shows that mTOR signalling in skeletal muscle fibres is critical for maintaining proper fibre innervation, preserving the NMJ structure in both the muscle fibre and the motor neuron. In addition, considering the beneficial effects of exercise in most pathologies affecting the NMJ, our findings suggest that part of these beneficial effects of exercise are through the well‐established activation of mTORC1 in skeletal muscle during and after exercise.

Highlights

In most cell types, the kinase mTOR is a major regulator of cellular metabolism, protein synthesis, and turnover.[1]
We recently showed that this inhibitory effect of rapamycin in skeletal muscle is due to the inhibition of the two best defined Mammalian Target of Rapamycin Complex 1 (mTORC1) targets: S6K1 and 4E-BP1.3 In addition to regulating increases in protein synthesis, multiple reports link mTORC1 signalling to protein breakdown
Reports suggested that enhancement of autophagic flux in adult skeletal muscle during catabolic conditions is mainly regulated by FoxO transcription factors,[4,5] while basal autophagy is modulated by mTORC1.6

Summary

Introduction

The kinase mTOR is a major regulator of cellular metabolism, protein synthesis, and turnover.[1]. It has been shown that mTOR can be found in two different complexes, that is, mTORC1 when bound to the scaffold protein. Raptor and mTORC2 when bound to the scaffold protein Rictor In skeletal muscle, both pharmacological and genetic interventions impinging on mTORC1 signalling have shown that modulation of the activity of this complex can have major effects on increases in muscle size and function. We recently showed that this inhibitory effect of rapamycin in skeletal muscle is due to the inhibition of the two best defined mTORC1 targets: S6K1 and 4E-BP1.3 In addition to regulating increases in protein synthesis, multiple reports link mTORC1 signalling to protein breakdown. It is well established that Mammalian Target of Rapamycin Complex 1 (mTORC1) signalling is a key modulator in mediating increases in skeletal muscle mass and function. Muscles at 1 and 7 months after deletion were analysed to assess muscle histology and muscle force

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Results

Discussion

Conclusion