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

ABSTRACT: OBJECTIVE:We examined whether skeletal muscle overexpression of PGC-1?1 or PGC-1?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?1 or PGC-1?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?1, but not PGC-1?4, increased NMJ formation and size. PGC-1?1 increased muscle secretion of neurturin, which was sufficient and necessary for the effects of muscle PGC-1?1 on NMJ formation. CONCLUSIONS:Our findings indicate that neurturin is a mediator of PGC-1?1-dependent retrograde signaling from muscle to motor neurons.

SUBMITTER: Mills R

PROVIDER: S-EPMC5784328 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Mills Richard R Taylor-Weiner Hermes H Correia Jorge C JC Agudelo Leandro Z LZ Allodi Ilary I Kolonelou Christina C Martinez-Redondo Vicente V Ferreira Duarte M S DMS Nichterwitz Susanne S Comley Laura H LH Lundin Vanessa V Hedlund Eva E Ruas Jorge L JL Teixeira Ana I AI

Molecular metabolism 20171107

<h4>Objective</h4>We examined whether skeletal muscle overexpression of PGC-1α1 or PGC-1α4 affected myokine secretion and neuromuscular junction (NMJ) formation.<h4>Methods</h4>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 tr ...[more]

PMID: 29157948

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Project description:Lipin 1 is an intracellular protein acting as a phosphatidic acid phosphohydrolase enzyme controlling lipid metabolism. Human recessive mutations in LPIN1 cause recurrent, early-onset myoglobinuria, a condition normally associated with muscle pain and weakness. Whether and how lipin 1 deficiency in humans leads to peripheral neuropathy is yet unclear. Herein, two novel compound heterozygous mutations in LPIN1 with neurological disorders, but no myoglobinuria were identified in an adult-onset syndromic myasthenia family. The present study sought to explore the pathogenic mechanism of LPIN1 in muscular and neural development. Methods: The clinical diagnosis of the proband was compared to the known 48 cases of LPIN1 recessive homozygous mutations. Whole-exome sequencing was carried out on the syndromic myasthenia family to identify the causative gene. The pathogenesis of lipin 1 deficiency during somitogenesis and neurogenesis was investigated using the zebrafish model. Whole-mount in situ hybridization, immunohistochemistry, birefringence analysis, touch-evoke escape response and locomotion assays were performed to observe in vivo the changes in muscles and neurons. The conservatism of the molecular pathways regulated by lipin 1 was evaluated in human primary glioblastoma and mouse myoblast cells by siRNA knockdown, drug treatment, qRT-PCR and Western blotting analysis. Results: The patient exhibited adult-onset myasthenia accompanied by muscle fiber atrophy and nerve demyelination without myoglobinuria. Two novel heterozygous mutations, c.2047A>C (p.I683L) and c.2201G>A (p.R734Q) in LPIN1, were identified in the family and predicted to alter the tertiary structure of LPIN1 protein. Lipin 1 deficiency in zebrafish embryos generated by lpin1 morpholino knockdown or human LPIN1 mutant mRNA injections reproduced the myotomes defects, a reduction both in primary motor neurons and secondary motor neurons projections, morphological changes of post-synaptic clusters of acetylcholine receptors, and myelination defects, which led to reduced touch-evoked response and abnormalities of swimming behaviors. Loss of lipin 1 function in zebrafish and mammalian cells also exhibited altered expression levels of muscle and neuron markers, as well as abnormally enhanced Notch signaling, which was partially rescued by the specific Notch pathway inhibitor DAPT. Conclusions: These findings pointed out that the compound heterozygous mutations in human LPIN1 caused adult-onset syndromic myasthenia with peripheral neuropathy. Moreover, zebrafish could be used to model the neuromuscular phenotypes due to the lipin 1 deficiency, where a novel pathological role of over-activated Notch signaling was discovered and further confirmed in mammalian cell lines.

Dataset Information

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

Publications

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

Similar Datasets

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