Neurturin is a PGC-1α1-controlled myokine that promotes motor neuron recruitment and neuromuscular junction formation

TY - JOUR

T1 - Neurturin is a PGC-1α1-controlled myokine that promotes motor neuron recruitment and neuromuscular junction formation

AU - Mills, Richard

AU - Taylor-Weiner, Hermes

AU - Correia, Jorge C

AU - Agudelo, Leandro Z

AU - Allodi, Ilary

AU - Kolonelou, Christina

AU - Martinez-Redondo, Vicente

AU - Ferreira, Duarte M S

AU - Nichterwitz, Susanne

AU - Comley, Laura H

AU - Lundin, Vanessa

AU - Hedlund, Eva

AU - Ruas, Jorge L

AU - Teixeira, Ana I

N1 - Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

PY - 2018/1

Y1 - 2018/1

N2 - OBJECTIVE: We examined whether skeletal muscle overexpression of PGC-1α1 or PGC-1α4 affected myokine secretion and neuromuscular junction (NMJ) formation.METHODS: A microfluidic device was used to model endocrine signaling and NMJ formation between primary mouse myoblast-derived myotubes and embryonic stem cell-derived motor neurons. Differences in hydrostatic pressure allowed for fluidic isolation of either cell type or unidirectional signaling in the fluid phase. Myotubes were transduced to overexpress PGC-1α1 or PGC-1α4, and myokine secretion was quantified using a proximity extension assay. Morphological and functional changes in NMJs were measured by fluorescent microscopy and by monitoring muscle contraction upon motor neuron stimulation.RESULTS: Skeletal muscle transduction with PGC-1α1, but not PGC-1α4, increased NMJ formation and size. PGC-1α1 increased muscle secretion of neurturin, which was sufficient and necessary for the effects of muscle PGC-1α1 on NMJ formation.CONCLUSIONS: Our findings indicate that neurturin is a mediator of PGC-1α1-dependent retrograde signaling from muscle to motor neurons.

AB - OBJECTIVE: We examined whether skeletal muscle overexpression of PGC-1α1 or PGC-1α4 affected myokine secretion and neuromuscular junction (NMJ) formation.METHODS: A microfluidic device was used to model endocrine signaling and NMJ formation between primary mouse myoblast-derived myotubes and embryonic stem cell-derived motor neurons. Differences in hydrostatic pressure allowed for fluidic isolation of either cell type or unidirectional signaling in the fluid phase. Myotubes were transduced to overexpress PGC-1α1 or PGC-1α4, and myokine secretion was quantified using a proximity extension assay. Morphological and functional changes in NMJs were measured by fluorescent microscopy and by monitoring muscle contraction upon motor neuron stimulation.RESULTS: Skeletal muscle transduction with PGC-1α1, but not PGC-1α4, increased NMJ formation and size. PGC-1α1 increased muscle secretion of neurturin, which was sufficient and necessary for the effects of muscle PGC-1α1 on NMJ formation.CONCLUSIONS: Our findings indicate that neurturin is a mediator of PGC-1α1-dependent retrograde signaling from muscle to motor neurons.

KW - Animals

KW - Cells, Cultured

KW - Mice

KW - Motor Neurons/cytology

KW - Mouse Embryonic Stem Cells/cytology

KW - Myoblasts/cytology

KW - Neural Stem Cells/cytology

KW - Neurogenesis

KW - Neuromuscular Junction/cytology

KW - Neurturin/metabolism

KW - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism

KW - Synaptic Transmission

U2 - 10.1016/j.molmet.2017.11.001

DO - 10.1016/j.molmet.2017.11.001

M3 - Journal article

C2 - 29157948

SN - 2212-8778

VL - 7

SP - 12

EP - 22

JO - Molecular Metabolism

JF - Molecular Metabolism

ER -