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

Richard Mills; Hermes Taylor-Weiner; Jorge C Correia; Leandro Z Agudelo; Ilary Allodi; Christina Kolonelou; Vicente Martinez-Redondo; Duarte M S Ferreira; Susanne Nichterwitz; Laura H Comley; Vanessa Lundin; Eva Hedlund; Jorge L Ruas; Ana I Teixeira

doi:10.1016/j.molmet.2017.11.001

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

Richard Mills, Hermes Taylor-Weiner, Jorge C Correia, Leandro Z Agudelo, Ilary Allodi, Christina Kolonelou, Vicente Martinez-Redondo, Duarte M S Ferreira, Susanne Nichterwitz, Laura H Comley, Vanessa Lundin, Eva Hedlund, Jorge L Ruas, Ana I Teixeira

Motor Control

10 Citations (Scopus)

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Abstract

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.

Original language	English
Journal	Molecular Metabolism
Volume	7
Pages (from-to)	12-22
Number of pages	11
ISSN	2212-8778
DOIs	https://doi.org/10.1016/j.molmet.2017.11.001
Publication status	Published - Jan 2018

Keywords

Animals
Cells, Cultured
Mice
Motor Neurons/cytology
Mouse Embryonic Stem Cells/cytology
Myoblasts/cytology
Neural Stem Cells/cytology
Neurogenesis
Neuromuscular Junction/cytology
Neurturin/metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
Synaptic Transmission

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10.1016/j.molmet.2017.11.001Licence: CC BY-NC-ND

Neurturin is a PGC-1α1-controlled myokine that promotes motor neuron recruitment and neuromuscular junction formationFinal published version, 2.26 MBLicence: CC BY-NC-ND

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Mills, R., Taylor-Weiner, H., Correia, J. C., Agudelo, L. Z., Allodi, I., Kolonelou, C., Martinez-Redondo, V., Ferreira, D. M. S., Nichterwitz, S., Comley, L. H., Lundin, V., Hedlund, E., Ruas, J. L., & Teixeira, A. I. (2018). Neurturin is a PGC-1α1-controlled myokine that promotes motor neuron recruitment and neuromuscular junction formation. Molecular Metabolism, 7, 12-22. https://doi.org/10.1016/j.molmet.2017.11.001

Mills, R, Taylor-Weiner, H, Correia, JC, Agudelo, LZ, Allodi, I, Kolonelou, C, Martinez-Redondo, V, Ferreira, DMS, Nichterwitz, S, Comley, LH, Lundin, V, Hedlund, E, Ruas, JL & Teixeira, AI 2018, 'Neurturin is a PGC-1α1-controlled myokine that promotes motor neuron recruitment and neuromuscular junction formation', Molecular Metabolism, vol. 7, pp. 12-22. https://doi.org/10.1016/j.molmet.2017.11.001

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

abstract = "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.",

keywords = "Animals, Cells, Cultured, Mice, Motor Neurons/cytology, Mouse Embryonic Stem Cells/cytology, Myoblasts/cytology, Neural Stem Cells/cytology, Neurogenesis, Neuromuscular Junction/cytology, Neurturin/metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism, Synaptic Transmission",

author = "Richard Mills and Hermes Taylor-Weiner and Correia, {Jorge C} and Agudelo, {Leandro Z} and Ilary Allodi and Christina Kolonelou and Vicente Martinez-Redondo and Ferreira, {Duarte M S} and Susanne Nichterwitz and Comley, {Laura H} and Vanessa Lundin and Eva Hedlund and Ruas, {Jorge L} and Teixeira, {Ana I}",

year = "2018",

month = jan,

doi = "10.1016/j.molmet.2017.11.001",

language = "English",

volume = "7",

pages = "12--22",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier",

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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

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 -

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

Abstract

Keywords

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