Journal
MOLECULAR METABOLISM
Volume 7, Issue -, Pages 12-22Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.molmet.2017.11.001
Keywords
Skeletal muscle; PGC-1 alpha; Neurturin; Motor neuron; Myokine
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Funding
- Human Frontier Science Program Young Investigator Award [RGY0082-2014]
- Whitaker International Program
- Wenner-Gren Foundation post-doctoral fellowship
- Ake Wiberg Stiftelse
- Strategic Research Area in Stem Cell Research and Regenerative Medicine at Karolinska Institutet
- Swedish Medical Research Council [2016-02112]
- Joint Program for Neurodegenerative Diseases [529-2014-7500]
- Ahlen-stiftelsen [mA1/h15]
- Magnus Bergvalls stiftelse [2015-00783]
- Strategic Research Area in Neuroscience at Karolinska Institutet (StratNeuro)
- Swedish Society for Medical Research
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Objective: We examined whether skeletal muscle overexpression of PGC-1 alpha 1 or PGC-1 alpha 4 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-1 alpha 1 or PGC-1 alpha 4, 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-1 alpha 1, but not PGC-1 alpha 4, increased NMJ formation and size. PGC-1 alpha 1 increased muscle secretion of neurturin, which was sufficient and necessary for the effects of muscle PGC-1 alpha 1 on NMJ formation. Conclusions: Our findings indicate that neurturin is a mediator of PGC-1 alpha 1-dependent retrograde signaling from muscle to motor neurons. (C) 2017 The Authors. Published by Elsevier GmbH.
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