Muscle Expression of SOD1G93A Modulates microRNA and mRNA Transcription Pattern Associated with the Myelination Process in the Spinal Cord of Transgenic Mice

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.

ALS and FTD: an epigenetic perspective

“…Interplay between different cell types is also being explored for pathogenic roles in neurodegeneration and evidence suggests that alterations in neighboring skeletal muscle may enhance damage to motor neurons in ALS [128]. Selectively expressing mutant SOD1 (G39A), a known mutation in ALS, in mouse muscles lead to altered expression of miRNAs and mRNAs associated with myelin homeostasis in the spinal cords of the mice, therefore revealing interplay between cell types affects epigenetic regulation [49]. …”

MicroRNAs as regulators of cell death mechanisms in amyotrophic lateral sclerosis

“…As noted above, the most constant finding in ALS rodent and human tissues is the increase in miR‐9 in the CNS and miR‐206 in skeletal muscle and serum …”

“…Several of the above cited miRNAs were found altered in SOD1G93A rodent muscle tissue; in particular, miR‐1, miR‐29, and miR‐133 were reduced compared to wild‐type. This local expression can influence the CNS mRNA patterns, particularly those linked with the myelination events in the spinal cord . Otherwise, higher expression of miR‐29a, which is specific for the CNS, has been observed from postnatal day 70 in the lumbar tract of the SOD1G3A mouse spinal cord compared to controls .…”

“…[18][19][20][21][22] The most constant finding in ALS mutant SOD1 rodents is an increase in miR-9 and miR-206. [23][24][25][26] In particular, the miR-9 level is increased in ALS rodent spinal cords, 24,26 whereas the miR-206 level is increased in skeletal muscles in both SOD1 and SMA murine models. 27 Remarkably, the reduction in miR-206 has a negative effect on the ALS disease course in mice, suggesting that it could exert a protective role.…”

Dysregulation of microRNA biogenesis machinery and microRNA/RNA ratio in skeletal muscle of amyotrophic lateral sclerosis mice

“…A large number of miRNAs are known to be dysregulated in various ALS tissues, with a global downregulation of miRNAs observed in motor neurons of patients with ALS . How these dysregulated miRNAs influence the disease onset, progression, and severity still requires experimental validation.…”