Muscle Expression of SOD1(G93A) Modulates microRNA and mRNA Transcription Pattern Associated with the Myelination Process in the Spinal Cord of Transgenic Mice.

Gabriella Dobrowolny,Marta Barba,Camilla Bernardini,Antonio Musarò,Martina Martini,Mirko Baranzini

doi:10.3389/fncel.2015.00463

Abstract

A crucial system severely affected in several neuromuscular diseases is the loss of effective connection between muscle and nerve, leading to a pathological non-communication between the two tissues. One of the best examples of impaired interplay between muscle and nerve is Amyotrophic Lateral Sclerosis, a neurodegenerative disease characterized by degeneration of motor neurons and muscle atrophy. Increasing evidences suggest that damage to motor neurons is enhanced by alterations in the neighboring non-neuronal cells and indicate that altered skeletal muscle might be the source of signals that impinge motor neuron activity and survival. Here we investigated whether muscle selective expression of SOD1G93A mutant gene modulates mRNAs and miRNAs expression at the level of spinal cord of MLC/SOD1G93A mice. Using a Taqman array, the Affymetrix Mouse Gene 2.0 ST approach and the MiRwalk 2.0 database, which provides information on miRNA and their predicted target genes, we revealed that muscle specific expression of SOD1G93A modulates relevant molecules of the genetic and epigenetic circuitry of myelin homeostasis in spinal cord of transgenic mice. Our study provides insights into the pathophysiological interplay between muscle and nerve and supports the hypothesis that muscle is a source of signals that can either positively or negatively affect the nervous system.

Highlights

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder in which the functional connection between nerve and muscle is severely compromised (Musarò, 2013)
We have previously demonstrated that muscle-specific expression of Superoxide dismutase 1 (SOD1) mutation in the MLC/SOD1G93A transgenic mouse model, which selectively expresses the mutant SOD1G93A gene in the skeletal muscle under the transcriptional control of a muscle-specific promoter (MLC), induces accumulation of Reactive Oxygen Species, causes muscle atrophy with a concomitant alteration in the ultrastructure and in the functional performance of skeletal muscles, and promotes microglia activation in the spinal cord, that is a presymptomatic sign of ALS disease (Dobrowolny et al, 2008b)
Nine up-regulated transcripts are involved in the myelination process such as Peripheral myelin protein 22 (Pmp22), Myelin protein zero (Mpz), Periaxin (Prx), the Early growth response 2 (Egr2) genes, Desert hedgehog (Dhh), or encode for extracellular matrix molecules such as Matrilin 2 (Matn2), Gliomedin (Gldn), Claudin 19 (Cldn19), and Smoothelin (Smtn)

Summary

Introduction

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder in which the functional connection between nerve and muscle is severely compromised (Musarò, 2013). We demonstrated that forced expression of muscle specific isoform of the Insulin Growth Factor-1 (mIGF-1) exclusively in the skeletal muscle of the global SOD1G93A mice counteracted the symptoms of ALS, induced satellite cell activation, stabilized neuromuscular junctions, preserved motor peripheral nerve, and led to a reduction in astrocytosis in the SOD1G93A spinal cord (Dobrowolny et al, 2005, 2008a). All together these data indicate that nervous development and homeostasis are intimately coupled to skeletal myogenesis and muscle function. We found that muscle specific expression of SOD1G93A gene affects spinal cord miRNome and transcriptome; in particular we observed the activation of genes involved in the myelination process and a decrease in the axon diameter to total fiber diameter in the sciatic nerve, suggesting a myelinopathy in the transgenic mouse model

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Conclusion