The TOR Pathway at the Neuromuscular Junction: More Than a Metabolic Player?

Perrine Castets,Daniel J Ham,Markus A Rüegg

doi:10.3389/fnmol.2020.00162

Perrine Castets, Daniel J Ham + Show 1 more

Open Access

https://doi.org/10.3389/fnmol.2020.00162

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Abstract

The neuromuscular junction (NMJ) is the chemical synapse connecting motor neurons and skeletal muscle fibers. NMJs allow all voluntary movements, and ensure vital functions like breathing. Changes in the structure and function of NMJs are hallmarks of numerous pathological conditions that affect muscle function including sarcopenia, the age-related loss of muscle mass and function. However, the molecular mechanisms leading to the morphological and functional perturbations in the pre- and post-synaptic compartments of the NMJ remain poorly understood. Here, we discuss the role of the metabolic pathway associated to the kinase TOR (Target of Rapamycin) in the development, maintenance and alterations of the NMJ. This is of particular interest as the TOR pathway has been implicated in aging, but its role at the NMJ is still ill-defined. We highlight the respective functions of the two TOR-associated complexes, TORC1 and TORC2, and discuss the role of localized protein synthesis and autophagy regulation in motor neuron terminals and sub-synaptic regions of muscle fibers and their possible effects on NMJ maintenance.

Highlights

Preserving muscle mass and function during aging has emerged as a major public health priority
While most Drosophila studies have implied an important function of TOR signaling in the pre-synaptic compartment, work in mice has demonstrated the importance of tightly controlled mTOR signaling in the post-synaptic compartment
The different focus on pre- and post-synaptic compartments between species may result from several factors, including the distinct nature of the chemical synapses, different neuromuscular junction (NMJ) organization and developmental mechanisms, stage of developmental analysis, and/or technical limitations relating to modulating factors in pre- and post- synaptic compartments

Summary

Introduction

Preserving muscle mass and function during aging has emerged as a major public health priority. While altered post-synaptic TOR signaling has little effect on the size and function of NMJs in Drosophila, activation of TOR, via the PI3K/TSC/Rheb branch, in motor neurons leads to overgrown NMJs (Martin-Pena et al, 2006; Knox et al, 2007; Natarajan et al, 2013). At 3 months of age, TSCmKO mice display increased fragmentation of the motor endplate (Figure 3D), with no sign of fiber degeneration, suggesting that constant activation of mTORC1 in muscle is deleterious for NMJ maintenance.

Results

Conclusion