Electromagnetic field-induced adaptive response in Schwann cells through DNA methylation, histone deacetylation, and oxidative stress.

Schwannomas are benign tumors of the peripheral nervous system arising from the transformation of Schwann cells (SCs). On the whole, these tumors are related to alterations of the neurofibromin type 2 gene, coding for the oncosuppressor merlin, a cytoskeleton-associated protein belonging to the ezrin-radixin-moesin family. However, the underlying mechanisms of schwannoma onset and progression are not fully elucidated, whereas one of the challenges might be the environment. In this light, the exposure to electromagnetic field (EMF), generated by the use of common electrical devices, has been defiantly suggested as the cause of SCs transformation even if the evidence was mostly epidemiologic. Indeed, insubstantial mechanisms have been so far identified to explain SCs oncotransformation. Recently, some in vitro evidence pointed out alterations in proliferation and migration abilities in SCs exposed to EMF (0.1 T, 50 Hz, 10 min). Here, we used the same experimental paradigma to discuss the involvement of putative epigenetic mechanisms in SCs adaptation to EMF and to explain the occurrence of hypoxic alterations after the exposure. Our findings indicate a set of environmental-induced changes in SCs, toward a less-physiological state, which may be pathologically relevant for the SCs differentiation and the schwannoma development.

Boosting the peripheral immune response in the skeletal muscles improved motor function in ALS transgenic mice.

Monocyte chemoattractant protein-1 (MCP1) is one of the most powerful pro-inflammatory chemokines. However, its signaling is pivotal in driving injured axon and muscle regeneration. We previously reported that MCP1 is more strongly upregulated in the nervous system of slow-progressing than fast-progressing SOD1G93A mice, the latter showing a poor immune response and eventual massive nerve and muscle degeneration. To assess the MCP1-mediated therapeutic role, we boosted the chemokine along the motor unit of the two SOD1G93A models through a single intramuscular injection of a scAAV9 vector engineered with the Mcp1 gene. We provided direct evidence underlying the pivotal role of the immune response in driving skeletal muscle regeneration and thus the speed of ALS progression. The comparative study performed in fast- and slow-progressing SOD1G93A mice spotlights the nature and temporal activation of the inflammatory response as limiting factors to preserve the periphery and interfere with the disease course. In addition, we recorded a novel pleiotropic role of MCP1 in promoting peripheral axon regeneration and modulating neuroinflammation, ultimately preventing neurodegeneration. Altogether, these observations highlight the immune response as a key determinant for disease variability and proffer a reasonable explanation for the failure of systemic immunomodulatory treatments, suggesting new potential strategies to hamper ALS progression.

Impact of Atorvastatin on Skeletal Muscle Mitochondrial Activity, Locomotion and Axonal Excitability-Evidence from ApoE-/- Mice.

The cardiovascular benefit of statins is well established. However, only 20% of high-risk patients remain adequately adherent after 5 years of treatment. Among reasons for discontinuation, statin associated-muscle pain symptoms are the most prevalent. Aim of the present study was to evaluate the impact of high dose atorvastatin on skeletal muscle mitochondrial activity, aerobic and anaerobic exercise, and axonal excitability in a murine model of atherosclerosis. ApoE-/- mice were fed 12 weeks a high-fat high-cholesterol diet alone or containing atorvastatin (40 mg/Kg/day). Outcomes were the evaluation of muscle mitochondrial functionality, locomotion, grip test, and axonal excitability (compound action potential recording analysis of Aα motor propioceptive, Aß mechanoceptive and C nociceptive fibres). Atorvastatin led to a reduction in muscle mitochondrial biogenesis and mitochondrial ATP production. It did not affect muscular strength but led to a time-dependent motor impairment. Atorvastatin altered the responsiveness of mechanoceptive and nociceptive fibres, respectively, the Aß and C fibres. These findings point out to a mild sensitization on mechanical, tactile and pain sensitivity. In conclusion, although the prevalence of muscular side effects from statins may be overestimated, understanding of the underlying mechanisms can help improve the therapeutic approach and reassure adherence in patients needing-to-be-treated.

Hearing loss and vestibular schwannoma: new insights into Schwann cells implication.

Hearing loss (HL) is the most common and heterogeneous disorder of the sensory system, with a large morbidity in the worldwide population. Among cells of the acoustic nerve (VIII cranial nerve), in the cochlea are present the hair cells, the spiral ganglion neurons, the glia-like supporting cells, and the Schwann cells (SCs), which alterations have been considered cause of HL. Notably, a benign SC-derived tumor of the acoustic nerve, named vestibular schwannoma (VS), has been indicated as cause of HL. Importantly, SCs are the main glial cells ensheathing axons and forming myelin in the peripheral nerves. Following an injury, the SCs reprogram, expressing some stemness features. Despite the mechanisms and factors controlling their biological processes (i.e., proliferation, migration, differentiation, and myelination) have been largely unveiled, their role in VS and HL was poorly investigated. In this review, we enlighten some of the mechanisms at the base of SCs transformation, VS development, and progression, likely leading to HL, and we pose great attention on the environmental factors that, in principle, could contribute to HL onset or progression. Combining the biomolecular bench-side approach to the clinical bedside practice may be helpful for the diagnosis, prediction, and therapeutic approach in otology.

Transcriptomic Profile Reveals Deregulation of Hearing-Loss Related Genes in Vestibular Schwannoma Cells Following Electromagnetic Field Exposure.

Hearing loss (HL) is the most common sensory disorder in the world population. One common cause of HL is the presence of vestibular schwannoma (VS), a benign tumor of the VIII cranial nerve, arising from Schwann cell (SC) transformation. In the last decade, the increasing incidence of VS has been correlated to electromagnetic field (EMF) exposure, which might be considered a pathogenic cause of VS development and HL. Here, we explore the molecular mechanisms underlying the biologic changes of human SCs and/or their oncogenic transformation following EMF exposure. Through NGS technology and RNA-Seq transcriptomic analysis, we investigated the genomic profile and the differential display of HL-related genes after chronic EMF. We found that chronic EMF exposure modified the cell proliferation, in parallel with intracellular signaling and metabolic pathways changes, mostly related to translation and mitochondrial activities. Importantly, the expression of HL-related genes such as NEFL, TPRN, OTOGL, GJB2, and REST appeared to be deregulated in chronic EMF exposure. In conclusion, we suggest that, at a preclinical stage, EMF exposure might promote the transformation of VS cells and contribute to HL.

Genomic and Non-genomic Action of Neurosteroids in the Peripheral Nervous System.

Since the former evidence of biologic actions of neurosteroids in the central nervous system, also the peripheral nervous system (PNS) was reported as a structure affected by these substances. Indeed, neurosteroids are synthesized and active in the PNS, exerting many important actions on the different cell types of this system. PNS is a target for neurosteroids, in their native form or as metabolites. In particular, old and recent evidence indicates that the progesterone metabolite allopregnanolone possesses important functions in the PNS, thus contributing to its physiologic processes. In this review, we will survey the more recent findings on the genomic and non-genomic actions of neurosteroids in nerves, ganglia, and cells forming the PNS, focusing on the mechanisms regulating the peripheral neuron-glial crosstalk. Then, we will refer to the physiopathological significance of the neurosteroid signaling disturbances in the PNS, in to identify new molecular targets for promising pharmacotherapeutic approaches.