Muscle Regulates mTOR Dependent Axonal Local Translation in Motor Neurons via CTRP3 Secretion: Implications for a Neuromuscular Disorder, Spinal Muscular Atrophy

Creator(s)

Wiebke A. Rehorst, University of Cologne
Maximilian P. Thelen, University of Cologne
Hendrik Nolte, University of Cologne
Clara Türk, University of Cologne
Sebahattin Cirak, Uniklinik Köln
Jonathan M. Peterson, Quillen-Dishner College of MedicineFollow
G. William Wong, Johns Hopkins University
Brunhilde Wirth, University of Cologne
Marcus Krüger, University of Cologne
Dominic Winter, Universität Bonn
Min Jeong Kye, University of Cologne

Document Type

Article

Publication Date

10-15-2019

Description

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder, which causes dysfunction/loss of lower motor neurons and muscle weakness as well as atrophy. While SMA is primarily considered as a motor neuron disease, recent data suggests that survival motor neuron (SMN) deficiency in muscle causes intrinsic defects. We systematically profiled secreted proteins from control and SMN deficient muscle cells with two combined metabolic labeling methods and mass spectrometry. From the screening, we found lower levels of C1q/TNF-related protein 3 (CTRP3) in the SMA muscle secretome and confirmed that CTRP3 levels are indeed reduced in muscle tissues and serum of an SMA mouse model. We identified that CTRP3 regulates neuronal protein synthesis including SMN via mTOR pathway. Furthermore, CTRP3 enhances axonal outgrowth and protein synthesis rate, which are well-known impaired processes in SMA motor neurons. Our data revealed a new molecular mechanism by which muscles regulate the physiology of motor neurons via secreted molecules. Dysregulation of this mechanism contributes to the pathophysiology of SMA.

Copyright Statement

The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Citation Information

Rehorst, Wiebke A.; Thelen, Maximilian P.; Nolte, Hendrik; Türk, Clara; Cirak, Sebahattin; Peterson, Jonathan M.; Wong, G. William; Wirth, Brunhilde; Krüger, Marcus; Winter, Dominic; and Kye, Min Jeong. 2019. Muscle Regulates mTOR Dependent Axonal Local Translation in Motor Neurons via CTRP3 Secretion: Implications for a Neuromuscular Disorder, Spinal Muscular Atrophy. Acta Neuropathologica Communications. Vol.7(1). https://doi.org/10.1186/s40478-019-0806-3 PMID: 31615574