ABSTRACT
BACKGROUND: Compartment syndrome following carbon monoxide (CO) poisoning and compression, can have a devastating impact on neuromuscular structures, depending on a time-based dosage. PURPOSE: To investigate multidimensional physiotherapy's short-term and long-term outcomes in identical twin cases who developed compartment syndrome due to CO poisoning and prolonged compression. STUDY DESIGN: Case report. METHODS: This study was conducted with two male cases, a 21-year-old identical twin. The loss of consciousness due to CO poisoning lasted for 15 hours. Case one had compartment syndrome that caused damage to the median and ulnar nerves in the right forearm, while Case two had compartment syndrome that caused damage to the radial nerve in the left forearm. No surgical intervention was performed (Fasciotomy etc). RESULTS: The disability, dexterity, hand health status, sensory-motor function, and edema were evaluated. Initial evaluations showed severe sensory and motor dysfunction, disability, and edema. Treatment included Complex decongestive physiotherapy, electrical stimulation, therapeutic ultrasound, orthotics, and exercises. On the 144th day (discharge day), both cases still exhibited weakness in functional strength and sensory loss compared to the uninjured side. At the ninth month, all parameters except strength were similar to the uninjured side in both cases. By the 53rd month, strength also reached normal values. CONCLUSIONS: Multidimensional physiotherapy effectively manages edema, improves sensory-motor function, and enhances hand function in the short and long term.
ABSTRACT
Hexanucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Due to the lack of trunk neuromuscular organoids (NMOs) from ALS patients' induced pluripotent stem cells (iPSCs), an organoid system was missing to model the trunk spinal neuromuscular neurodegeneration. With the C9orf72 ALS patient-derived iPSCs and isogenic controls, we used an NMO system containing trunk spinal cord neural and peripheral muscular tissues to show that the ALS NMOs could model peripheral defects in ALS, including contraction weakness, neural denervation, and loss of Schwann cells. The neurons and astrocytes in ALS NMOs manifested the RNA foci and dipeptide repeat proteins. Acute treatment with the unfolded protein response inhibitor GSK2606414 increased the glutamatergic muscular contraction 2-fold and reduced the dipeptide repeat protein aggregation and autophagy. This study provides an organoid system for spinal neuromuscular pathologies in ALS and its application for drug testing.
Subject(s)
Amyotrophic Lateral Sclerosis , Frontotemporal Dementia , Humans , Amyotrophic Lateral Sclerosis/pathology , C9orf72 Protein/genetics , C9orf72 Protein/metabolism , Frontotemporal Dementia/genetics , Frontotemporal Dementia/pathology , Proteins/genetics , Dipeptides/pharmacology , Dipeptides/metabolism , DNA Repeat ExpansionABSTRACT
BACKGROUND: The increased expression of the nicotinic acetylcholine receptor (nAChR) in muscle denervation is thought to be associated with electrophysiological acetylcholine supersensitivity after nerve injury. Hence, we investigated the utility of the 18F-ASEM alpha7-nAChR targeting radiotracer as a new diagnostic method by visualizing skeletal muscle denervation in mouse models of sciatic nerve injury. METHODS: Ten-week-old C57BL/6 male mice were utilized. The mice were anesthetized, and the left sciatic nerve was resected after splitting the gluteal muscle. One week (n = 11) and three weeks (n = 6) after the denervation, 18F-ASEM positron emission tomography/magnetic resonance imaging (PET/MRI) was acquired. Maximum standardized uptake values (SUVmax) of the tibialis anterior muscle were measured for the denervated side and the control side. Autoradiographic evaluation was performed to measure the mean counts of the denervated and control tibialis anterior muscles at one week. In addition, immunohistochemistry was used to identify alpha7-nAChR-positive areas in denervated and control tibialis anterior muscles at one week (n = 6). Furthermore, a blocking study was conducted with methyllycaconitine (MLA, n = 5). RESULTS: 18F-ASEM PET/MRI showed significantly increased 18F-ASEM uptake in the denervated tibialis anterior muscle relative to the control side one week and three weeks post-denervation. SUVmax of the denervated muscles at one week and three weeks showed significantly higher uptake than the control (P = 0.0033 and 0.0277, respectively). The relative uptake by autoradiography for the denervated muscle was significantly higher than in the control, and immunohistochemistry revealed significantly greater alpha7-nAChR expression in the denervated muscle (P = 0.0277). In addition, the blocking study showed no significant 18F-ASEM uptake in the denervated side when compared to the control (P = 0.0796). CONCLUSIONS: Our results suggest that nAChR imaging with 18F-ASEM has potential as a noninvasive diagnostic method for peripheral nervous system disorders.
ABSTRACT
The Neuropathy Score Reporting and Data System (NS-RADS) is a newly developed MR imaging-based classification that standardizes reporting and multidisciplinary communication for MR imaging diagnosis and follow-up of peripheral neuropathies. NS-RADS classification has shown to be accurate and reliable across different centers, readers' experience levels, and degrees of peripheral neuropathies, which include nerve injury, entrapment, neoplasm, diffuse neuropathy, post-interventional status, and temporal changes in muscle denervation. This article brings a practical review of NS-RADS classification, representative MR cases, and a step-by-step tutorial on how to approach this staging system. Readers can gain knowledge and apply it in their practice, aiming to standardize the communications between specialties and improve patient management.
Subject(s)
Peripheral Nervous System Diseases , Humans , Peripheral Nervous System Diseases/diagnostic imaging , Magnetic Resonance ImagingABSTRACT
Introduction: Conservative treatment of peripheral nerve injuries is based on physical therapy approaches, including electrostimulation of denervated muscle. Electrostimulation retards denervation atrophy and prolongs the time window for axon reinnervation. Aim: This article focuses on the potential of electroacupuncture, which combines electrostimulation with acupuncture, in the context of the latest knowledge on the mechanisms of axonal regeneration. Results and conclusions: The possibilities of influencing the growth rate of the axon itself through neurotrophic factors have primarily been previously proven in rodent models. Electroacupuncture as mini-invasive electrostimulation using acupuncture needles appears to be a promising option for the treatment of peripheral nerve paresis. However, this therapy needs to be evaluated in the context of human medicine.
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BACKGROUND: It is assumed that in patients with diabetic neuropathy, muscle denervation can result in shoulder disorders. Muscle denervation will lead to changes in muscle architecture, which can be assessed by quantitative muscle ultrasound (QMUS). The aim was to investigate whether increased muscle echogenicity, as a sign of neuropathy, is more often present in patients with shoulder pain who have type 2 diabetes mellitus (T2DM) than in those without. METHODS: Sixty-six patients with T2DM and 23 patients without diabetes mellitus (DM) having shoulder pain were included. Quantitative muscle ultrasound images were obtained bilaterally from the biceps brachii, deltoid, and supra- and infraspinatus muscles. The mean echogenicity (muscle ultrasound grey value) was transformed into z-scores and compared to reference values obtained from 50 healthy participants. Associations between muscle echogenicity and clinical variables were explored. RESULTS: In painful shoulders of both patients with T2DM and patients without DM, mean echogenicity z-scores of all muscles were significantly increased compared to healthy controls. No significant differences in echogenicity between patients with T2DM and those without DM were found. In patients with T2DM, a distal symmetric polyneuropathy was significantly associated with increased echogenicity of all muscles except the infraspinatus muscle. CONCLUSIONS: These findings indicate that patients with painful shoulders, irrespective of having T2DM, seem to have abnormal shoulder muscles. Future studies are needed to elucidate whether neuropathy or other conditions lead to these muscle changes.
Subject(s)
Diabetes Mellitus, Type 2 , Shoulder Pain , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnostic imaging , Humans , Muscle, Skeletal/diagnostic imaging , Rotator Cuff/diagnostic imaging , Shoulder Pain/diagnostic imaging , Shoulder Pain/etiology , Ultrasonography/methodsABSTRACT
OBJECTIVE: The purpose of this study was to investigate whether photobiomodulation (PBM) can protect against and attenuate muscle atrophy owing to complete peripheral nerve lesion in mice by acting on autophagy. METHODS: C57BL/10 mice underwent right sciatic nerve transection to induce tibialis anterior muscle atrophy. After 6 hours of denervation, the mice received PBM (wavelength, 830 nm) daily, transcutaneously over the tibialis anterior muscle region for 5 or 14 days. Some mice with sciatic nerve lesion did not receive PBM. Mice that did not have sciatic nerve lesion and PBM were used as controls. After 5 and 14 days, the right tibialis anterior muscle was examined using histomorphometric (cross-sectional area of muscle fibers), Western blot (levels of the autophagy marker LC3), and immunofluorescence analyses (number of LC3 puncta in the muscle fibers). RESULTS: The cross-sectional area of the tibialis anterior muscle fibers decreased after 5 and 14 days of denervation. PBM protected against muscle fiber atrophy after 5 days of denervation and attenuated muscle fiber atrophy after 14 days of denervation. After 5 days of muscle denervation, autophagy did not change, as demonstrated by the comparable levels of LC3-I/II ratio and LC3 puncta between the controls and the mice with atrophic muscle; PBM did not change this profile. After 14 days of denervation, an increased LC3-I/II ratio suggested an ongoing autophagy, which was not affected by PBM. CONCLUSION: PBM attenuated the tibialis anterior muscle atrophy induced by sciatic nerve transection in the mice after at least 5 and 14 days of muscle denervation, without affecting autophagy. The transient protective effect of PBM was observed as early as 5 days after the of complete nerve lesion.
Subject(s)
Muscular Atrophy , Sciatic Neuropathy , Animals , Autophagy , Mice , Mice, Inbred C57BL , Muscle Denervation , Muscle, Skeletal/innervation , Muscular Atrophy/pathologyABSTRACT
BACKGROUND: Quantitative MRI (qMRI) metrics reflect microstructural skeletal muscle changes secondary to denervation and may correspond to conventional electromyography (EMG) assessments of motor unit recruitment (MUR) and denervation. HYPOTHESIS: Differences in quantitative T2 , diffusion-based apparent fiber diameter (AFD), and fat fraction (FF) exist between EMG grades, in patients with clinically suspected neuropathy of the brachial plexus. STUDY TYPE: Prospective. POPULATION: A total of 30 subjects (age = 37.5 ± 17.5, 21M/9F) with suspected brachial plexopathy. FIELD STRENGTH/SEQUENCE: 3-Tesla; qMRI using fast spin echo (T2 -mapping), multi-b-valued diffusion-weighted echo planar imaging (for AFD), and dual-echo Dixon gradient echo (FF-mapping) sequences. ASSESSMENT: qMRI values were compared against EMG grades (MUR and denervation). qMRI values (T2 , AFD, and FF) were obtained for five regional shoulder muscles. A 4-point scale was used for MUR/denervation severity. STATISTICAL TESTS: Linear mixed models and least-squares pairwise comparisons were used to evaluate qMRI differences between EMG grades. Predictive accuracy of EMG grades from qMRI was quantified by 10-fold cross-validated logistic models. A P value < 0.05 was considered statistically significant. RESULTS: Mean (95% confidence interval) qMRI for "full" MUR were T2 = 39.40 msec (35.72-43.08 msec), AFD = 78.35 µm (72.52-84.19 µm), and FF = 4.54% (2.11-6.97%). Significant T2 increases (+8.36 to +14.67 msec) and significant AFD decreases (-11.04 to -21.58 µm) were observed with all abnormal MUR grades as compared to "full" MUR. Significant changes in both T2 and AFD were observed with increased denervation (+9.59 to +15.04 msec, -16.25 to -18.66 µm). There were significant differences in FF between some MUR grades (-1.45 to +2.96%), but no significant changes were observed with denervation (P = 0.089-0.662). qMRI prediction of abnormal MUR or denervation was strong (mean accuracy = 0.841 and 0.810, respectively) but moderate at predicting individual grades (accuracy = 0.492 and 0.508, respectively). DATA CONCLUSION: Quantitative T2 and AFD differences were observed between EMG grades in assessing muscle denervation. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.
Subject(s)
Brachial Plexus , Magnetic Resonance Imaging , Brachial Plexus/diagnostic imaging , Electromyography , Humans , Magnetic Resonance Imaging/methods , Muscle, Skeletal/diagnostic imaging , Prospective StudiesABSTRACT
BACKGROUND: In breast reconstruction with a latissimus dorsi flap, immediate fat grafting is useful for increasing flap volume. However, factors such as latissimus dorsi muscle atrophy and fat graft retention affect the volume of the reconstructed breast, and reports are inconsistent regarding treatment of the thoracodorsal nerve. This study examined how thoracodorsal nerve treatment affects the rates of latissimus dorsi flap preservation and fat graft retention using a rat model. METHODS: Fat harvested from the inguinal region was grafted to the latissimus dorsi muscle elevated as a pedicled muscle flap on the experimental side and to the intact LD muscle on the contralateral side (control). Rats were divided into intact thoracodorsal nerve (Ni), temporary denervation (Ntd), and permanent denervation (Npd) groups (n = 8 each). Fat retention and muscle preservation rates were determined, and histological changes were analyzed postoperatively. RESULTS: Fat retention rates did not significantly differ between the Ni and Ntd groups. Only the Npd group showed a significant decrease in fat retention rate relative to the control side (p < 0.01). The quality of the grafted fat as reflected by histological parameters was significantly lower, and the viable adipocyte area and muscle fiber preservation rate significantly decreased, in the Npd group compared to the other groups. CONCLUSIONS: Permanent thoracodorsal nerve denervation resulted in severe muscle atrophy and a significantly decreased fat retention rate. Temporary denervation had no significant benefit, suggesting that preserving the thoracodorsal nerve may be desirable for achieving sufficient volume in latissimus dorsi flap breast reconstruction with immediate fat grafting. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Subject(s)
Mammaplasty , Superficial Back Muscles , Animals , Mammaplasty/methods , Muscle Denervation , Muscular Atrophy/surgery , Rats , Superficial Back Muscles/transplantationABSTRACT
BACKGROUND: To develop and evaluate a diffusion MRI-based apparent muscle fiber diameter (AFD) method in patients with muscle denervation. It was hypothesized that AFD differences between denervated, non-denervated and control muscles would be greater than those from standard diffusion metrics. METHODS: A spin-echo diffusion acquisition with multi-b-valued diffusion sampling was used. An orientation-invariant dictionary approach utilized a cylinder-based forward model and multi-compartment model for obtaining restricted and free fractions. Simulations were performed to determine precision, bias, and optimize dictionary parameters. In all, 18 exams of patients with muscle denervation and 8 exams of healthy subjects were performed at 3T. Six regions of interests (ROIs) within separate shoulder muscles were selected, yielding three groups consisting 47 control (healthy), 36 non-denervated (patients), and 68 denervated (patients) muscle ROIs. Two-sample t-tests (α=0.05) between groups were performed with Holm-Bonferroni correction. T2- and fat fraction (FF)-mapping were acquired for comparison. RESULTS: Mean AFD was 89.7±13.6 µm in control, 71.6±15.3 µm in non-denervated, and 60.7±15.9 µm in denervated muscles and were significantly different (P<0.001) in paired comparisons and in 10/12 individual muscle region comparisons. Correlation between AFD and FF (-0.331, P<0.001) was low, but correlation between FA and FF was negligible (0.197, P=0.016). Correlation was low between AFD and T2 (-0.395, P<0.001) and between FA and T2 (0.359, P<0.001). CONCLUSIONS: Diffusion MRI-based AFD complements T2- and FF-mapping techniques to non-invasively assess muscle denervation.
ABSTRACT
Introduction: Botulinumtoxin associated muscle denervation (BNTMD) can be detected by magnet resonance imaging (MRI), MRI may provide further insights into the exact timeline of BNTMD and the potential impact and timing of physical exercise. We aimed to assess the time interval until detection of BNTMD by MRI and whether immediate physical exercise after intramuscular BNT injection has a measurable effect on clinical parameters and the intramuscular denervation dynamics illustrated by MRI. Materials and Methods: Eleven age-matched patients were randomized to an "exercise" or "no-exercise" group. Eighty mouse-units of incobotulinumtoxin were injected into the spastic biceps muscle. MRI of the injected region, hand-held dynamometry of elbow flexor strength and clinical rating scales (mAS, CGI-I) were conducted in predefined intervals. Results: We could not detect BNTMD within 24 h but 7 days after injection independent of group allocation (exercise n = 6, no-exercise n = 5). Denervation signs were more diffuse and spread into adjacent muscles in patients having received exercise. We could not detect differences concerning clinical measures between the two groups. Conclusions: Physical exercise might influence BNTMD dynamics and promote propagation of T2-MR muscle denervation signs from the injected site into adjacent muscles. Trial registration: clinicaltrialsregister.eu, Identifier 2017-003117-25.
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BACKGROUND: The C22 mouse is a Charcot-Marie-Tooth 1A transgenic model with minimal axonal loss. OBJECTIVE: To analyse early skeletal muscle changes resulting from this dysmyelinating neuropathy. METHODS: Histology of tibialis anterior muscles of C22 mice and wild type litter mate controls for morphometric analysis and (immuno-)histochemistry for known denervation markers and candidate proteins identified by representational difference analysis (RDA) based on mRNA from the same muscles; quantitative PCR and Western blotting for confirmation of RDA findings. RESULTS: At age 10 days, morphometry was not different between groups, while at 21 days, C22 showed significantly more small diameter fibres, indicating the onset of atrophy at an age when weakness becomes detectable. Neither (immuno-)histochemistry nor RDA detected extrajunctional expression of acetylcholine receptors by age 10 and 21 days, respectively. RDA identified some mRNA up-regulated in C22 muscles, among them at 10 days, prior to detectable weakness or atrophy, integral membrane protein 2a (Itm2a), eukaryotic initiation factor 2, subunit 2 (Eif2s2) and cytoplasmic phosphatidylinositol transfer protein 1 (Pitpnc1). However, qPCR failed to measure significant differences. In contrast, Itm2a and Eif2s2 mRNA were significantly down-regulated comparing 21 versus 10 days of age in both groups, C22 and controls. Western blotting confirmed significant down-regulation of ITM2A protein in C22 only. CONCLUSION: Denervation-like changes in this model develop slowly with onset of atrophy and weakness at about three weeks of age, before detection of extrajunctional acetylcholine receptors. Altered Itm2a expression seems to begin early as an increase, but becomes distinct as a decrease later.
Subject(s)
Charcot-Marie-Tooth Disease/pathology , Muscle, Skeletal/pathology , Animals , Disease Models, Animal , Female , Humans , Membrane Transport Proteins , Mice , PhenotypeABSTRACT
ALS is a fatal neurodegenerative disease that is associated with muscle atrophy, motoneuron degeneration and denervation. Different mechanisms have been proposed to explain the pathogenesis of the disease; in this context, microRNAs have been described as biomarkers and potential pathogenetic factors for ALS. MyomiRs are microRNAs produced by skeletal muscle, and they play an important role in tissue homeostasis; moreover, they can be released in blood circulation in pathological conditions, including ALS. However, the functional role of myomiRs in muscle denervation has not yet been fully clarified. In this study, we analyze the levels of two myomiRs, namely miR-206 and miR-133a, in skeletal muscle and blood samples of denervated mice, and we demonstrate that surgical denervation reduces the expression of both miR-206 and miR-133a, while miR-206 but not miR-133a is upregulated during the re-innervation process. Furthermore, we quantify the levels of miR-206 and miR-133a in serum samples of two ALS mouse models, characterized by different disease velocities, and we demonstrate a different modulation of circulating myomiRs during ALS disease, according to the velocity of disease progression. Moreover, taking into account surgical and pathological denervation, we describe a different response to increasing amounts of circulating miR-206, suggesting a hormetic effect of miR-206 in relation to changes in neuromuscular communication.
Subject(s)
Amyotrophic Lateral Sclerosis/pathology , MicroRNAs/blood , Muscle, Skeletal/metabolism , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/surgery , Animals , Biomarkers/metabolism , Disease Models, Animal , Disease Progression , Gene Expression Regulation , Mice , Mice, Inbred C57BL , Mice, Transgenic , MicroRNAs/metabolism , Muscle Denervation , Muscle, Skeletal/innervation , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolismABSTRACT
This preliminary research determines whether a combination of reverse end-to-side neurorrhaphy and rapamycin treatment achieves a better functional outcome than a single application after prolonged peripheral nerve injury. We found that the tibial nerve function of the reverse end-to-side + rapamycin group recovered better, with a higher tibial function index value, higher amplitude recovery rate, and shorter latency delay rate (P < 0.05). The reverse end-to-side + rapamycin group better protected the gastrocnemius muscle with more forceful contractility, tetanic tension, and a higher myofibril cross-sectional area (P < 0.05). Combining reverse end-to-side neurorrhaphy with rapamycin treatment is a practical approach to promoting the recovery of chronically denervated muscle atrophy after peripheral nerve injury.
Subject(s)
Anti-Bacterial Agents/pharmacology , Muscle, Skeletal/physiopathology , Nerve Regeneration/physiology , Neurosurgical Procedures , Peripheral Nerve Injuries/therapy , Sirolimus/pharmacology , Tibial Neuropathy/therapy , Animals , Anti-Bacterial Agents/administration & dosage , Combined Modality Therapy , Disease Models, Animal , Electromyography , Female , Muscle Denervation , Peripheral Nerve Injuries/drug therapy , Peripheral Nerve Injuries/surgery , Rats , Rats, Sprague-Dawley , Sirolimus/administration & dosage , Tibial Neuropathy/drug therapy , Tibial Neuropathy/surgeryABSTRACT
Spinal muscular atrophy (SMA) is a heritable, autosomal recessive neuromuscular disorder characterized by a loss of the survival of motor neurons (SMN) protein, which leads to degeneration of lower motor neurons, and muscle atrophy. Despite SMA being nosographically classified as a motor neuron disease, recent advances indicate that peripheral alterations at the level of the neuromuscular junction (NMJ), involving the muscle, and axons of the sensory-motor system, occur early, and may even precede motor neuron loss. In the present study, we used a mouse model of slow progressive (type III) SMA, whereby the absence of the mouse SMN protein is compensated by the expression of two human genes (heterozygous SMN1A2G, and SMN2). This leads to late disease onset and prolonged survival, which allows for dissecting slow degenerative steps operating early in SMA pathogenesis. In this purely morphological study carried out at transmission electron microscopy, we extend the examination of motor neurons and proximal axons towards peripheral components, including distal axons, muscle fibers, and also muscle spindles. We document remarkable ultrastructural alterations being consistent with early peripheral denervation in SMA, which may shift the ultimate anatomical target in neuromuscular disease from the spinal cord towards the muscle. This concerns mostly mitochondrial alterations within distal axons and muscle, which are quantified here through ultrastructural morphometry. The present study is expected to provide a deeper knowledge of early pathogenic mechanisms in SMA.
Subject(s)
Muscular Atrophy, Spinal , Spinal Muscular Atrophies of Childhood , Animals , Denervation , Disease Models, Animal , Mice , Motor Neurons , Muscular Atrophy, Spinal/genetics , Neuromuscular JunctionABSTRACT
The SCN5A gene encodes the α-subunit of the voltage-gated cardiac sodium channel (NaV1.5), a key player in cardiac action potential depolarization. Genetic variants in protein-coding regions of the human SCN5A have been largely associated with inherited cardiac arrhythmias. Increasing evidence also suggests that aberrant expression of the SCN5A gene could increase susceptibility to arrhythmogenic diseases, but the mechanisms governing SCN5A expression are not yet well understood. To gain insights into the molecular basis of SCN5A gene regulation, we used rat gastrocnemius muscle four days following denervation, a process well known to stimulate Scn5a expression. Our results show that denervation of rat skeletal muscle induces the expression of the adult cardiac Scn5a isoform. RNA-seq experiments reveal that denervation leads to significant changes in the transcriptome, with Scn5a amongst the fifty top upregulated genes. Consistent with this increase in expression, ChIP-qPCR assays show enrichment of H3K27ac and H3K4me3 and binding of the transcription factor Gata4 near the Scn5a promoter region. Also, Gata4 mRNA levels are significantly induced upon denervation. Genome-wide analysis of H3K27ac by ChIP-seq suggest that a super enhancer recently described to regulate Scn5a in cardiac tissue is activated in response to denervation. Altogether, our experiments reveal that similar mechanisms regulate the expression of Scn5a in denervated muscle and cardiac tissue, suggesting a conserved pathway for SCN5A expression among striated muscles.
Subject(s)
Epigenesis, Genetic , Muscle Denervation , Muscle, Skeletal/metabolism , NAV1.5 Voltage-Gated Sodium Channel/biosynthesis , Response Elements , Transcriptome , Animals , GATA4 Transcription Factor/genetics , GATA4 Transcription Factor/metabolism , Male , Muscle, Skeletal/innervation , Muscle, Skeletal/pathology , RNA-Seq , Rats , Rats, Sprague-DawleyABSTRACT
Action potential is transmitted to muscle fibers through specialized synaptic interfaces called neuromuscular junctions (NMJs). These structures are capped by terminal Schwann cells (tSCs), which play essential roles during formation and maintenance of the NMJ. tSCs are implicated in the correct communication between nerves and muscles, and in reinnervation upon injury. During aging, loss of muscle mass and strength (sarcopenia and dynapenia) are due, at least in part, to the progressive loss of contacts between muscle fibers and nerves. Despite the important role of tSCs in NMJ function, very little is known on their implication in the NMJ-aging process and in age-associated denervation. This review summarizes the current knowledge about the implication of tSCs in the age-associated degeneration of NMJs. We also speculate on the possible mechanisms underlying the observed phenotypes.
ABSTRACT
Functional recovery following peripheral nerve injury worsens with increasing durations of delay prior to repair. From the time of injury until re-innervation occurs, denervated muscle undergoes progressive atrophy that limits the extent to which motor function can be restored. Similarly, Schwann cells (SC) in the distal nerve lacking axonal interaction progressively lose their capacity to proliferate and support regenerating axons. The relative contributions of these processes to diminished functional recovery is unclear. We developed a novel rat model to isolate the effects of SC vs. muscle denervation on functional recovery. Four different groups underwent the following interventions for 12 weeks prior to nerve transfer: 1) muscle denervation; 2) SC denervation; 3) muscle + SC denervation (negative control); 4) no denervation (positive control). Functional recovery was measured weekly using the stimulated grip strength testing (SGST). Animals were sacrificed 13 weeks post nerve transfer. Retrograde labeling was used to assess the number of motor neurons that regenerated their axons. Immunofluorescence was performed to evaluate target muscle re-innervation and atrophy, and to assess the phenotype of the SC within the distal nerve segment. Functional recovery in the muscle denervation and SC denervation groups mirrored that of the negative and positive control groups, respectively. The SC denervation group achieved better functional recovery, with a greater number of reinnervated motor endplates and less muscle atrophy, than the muscle denervation group. Retrograde labeling suggested a higher number of neurons contributing to muscle reinnervation in the muscle denervation group as compared to SC denervation (p > 0.05). The distal nerve segment in the muscle denervation group had a greater proportion of SCs expressing the proliferation marker Ki67 as compared to the SC denervation group (p < 0.05). Conversely, the SC denervation group had a higher percentage of senescent SCs expressing p16 as compared to the muscle denervation group (p < 0.05). The deleterious effects of muscle denervation are more consequential than the effects of SC denervation on functional recovery. The effects of 12 weeks of SC denervation on functional outcome were negligible. Future studies are needed to determine whether longer periods of SC denervation negatively impact functional recovery.
Subject(s)
Median Nerve/physiology , Muscle Denervation/methods , Nerve Regeneration/physiology , Recovery of Function/physiology , Schwann Cells/physiology , Ulnar Nerve/physiology , Animals , Hand Strength/physiology , Male , Median Nerve/transplantation , Muscle Denervation/trends , Muscular Atrophy , Peripheral Nerve Injuries/pathology , Peripheral Nerve Injuries/surgery , Rats , Rats, Inbred Lew , Ulnar Nerve/transplantationABSTRACT
Guillain-Barré syndrome (GBS) is an autoimmune peripheral neuropathy and a common cause of neuromuscular paralysis. Preceding infection induces the production of anti-ganglioside (GD) antibodies attacking its own peripheral nerves. In severe proximal peripheral nerve injuries that require long-distance axon regeneration, motor functional recovery is virtually nonexistent. Damaged axons fail to regrow and reinnervate target muscles. In mice, regenerating axons must reach the target muscle within 35â¯days (critical period) to reform functional neuromuscular junctions and regain motor function. Successful functional recovery depends on the rate of axon regeneration and debris removal (Wallerian degeneration) after nerve injury. The innate-immune response of the peripheral nervous system to nerve injury such as timing and magnitude of cytokine production is crucial for Wallerian degeneration. In the current study, forced expression of human heat shock protein (hHsp) 27 completely reversed anti-GD-induced inhibitory effects on nerve repair assessed by animal behavioral assays, electrophysiology and histology studies, and the beneficial effect was validated in a second mouse line of hHsp27. The protective effect of hHsp27 on prolonged muscle denervation was examined by performing repeated sciatic nerve crushes to delay regenerating axons from reaching distal muscle from 37â¯days up to 55â¯days. Strikingly, hHsp27 was able to extend the critical period of motor functional recovery for up to 55â¯days and preserve the integrity of axons and mitochondria in distal nerves. Cytokine array analysis demonstrated that a number of key cytokines which are heavily involved in the early phase of innate-immune response of Wallerian degeneration, were found to be upregulated in the sciatic nerve lysates of hHsp27 Tg mice at 1â¯day postinjury. However, persistent hyperinflammatory mediator changes were found after chronic denervation in sciatic nerves of littermate mice, but remained unchanged in hHsp27 Tg mice. Taken together, the current study provides insight into the development of therapeutic strategies to enhance muscle receptiveness (reinnervation) by accelerating axon regeneration and Wallerian degeneration.