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

Mol Metab. 2018 Jan;7:12-22. doi: 10.1016/j.molmet.2017.11.001. Epub 2017 Nov 7.

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: Motor neuron; Myokine; Neurturin; PGC-1α; Skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Neurturin
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse