Peripheral nerve injuries represent a substantial clinical problem with insufficient or unsatisfactory treatment options. This review summarises all the events occurring after nerve damage at the ...level of the cell body, the site of injury and the target organ. Various experimental strategies to improve neuronal survival, axonal regeneration and target reinnervation are described including pharmacological approaches and cell-based therapies. Given the complexity of nerve regeneration, further studies are needed to address the biology of nerve injury, to improve the interaction with implantable scaffolds, and to implement cell-based therapies in nerve tissue engineering.
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The purpose of this study was to investigate the effect of massage therapy on retarding denervated muscle atrophy in rabbits.
The denervated skeletal muscle atrophy rabbit model was established with ...the clamping rabbit tibial nerve method. On the third and first day after clamping the rabbit tibial nerve, the model rabbits were treated with massage or nerve growth factor (15 μg/mL) once a day for 8 weeks, respectively. Subsequently, gastrocnemius tissues were collected from rabbits and detected by electromyography. The gastrocnemius tissue sections were stained with hematoxylin and eosin and Sirius red staining to evaluate the histopathologic damage of denervated muscle atrophy in a rabbit model. Furthermore, the proliferation and differentiation-related targets of satellite cells in gastrocnemius tissues were detected by immunohistochemical, immunofluorescence, real-time quantitative reverse transcription polymerase chain reaction, and Western blot assays, respectively. Also, the effects of massage on the Wnt/β-catenin pathway were detected. Finally, gastrocnemius myocytes were isolated from rabbits to detect the expression levels of α-smooth muscle actin (α-SMA).
The nerve conduction deteriorated continuously with time in model rabbits. Massage significantly ameliorated the pathologic damages and motor endplate microstructure of gastrocnemius muscle, effectively prevented fibrosis, and regulated the proliferation and differentiation-related messenger RNA and protein expression of satellite cells with the time increased after denervation. Additionally, the number of differentiating satellite cells was increased after being treated with massage, and massage further kept denervated muscles from atrophy. Importantly, the effect of massage to attenuate muscle atrophy was associated with the activation of the Wnt/β-catenin pathway. Meanwhile, massage reduced the expression of α-SMA in gastrocnemius myocytes.
This model demonstrated that massage delayed the atrophy of skeletal muscle. This was probably accomplished by regulating the proliferation and differentiation of the satellite cells via the Wnt/β-catenin signaling pathway.
Compartment syndrome following carbon monoxide (CO) poisoning and compression, can have a devastating impact on neuromuscular structures, depending on a time-based dosage.BACKGROUNDCompartment ...syndrome following carbon monoxide (CO) poisoning and compression, can have a devastating impact on neuromuscular structures, depending on a time-based dosage.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.PURPOSETo 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.Case report.STUDY DESIGNCase report.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).METHODSThis 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).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.RESULTSThe 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.Multidimensional physiotherapy effectively manages edema, improves sensory-motor function, and enhances hand function in the short and long term.CONCLUSIONSMultidimensional physiotherapy effectively manages edema, improves sensory-motor function, and enhances hand function in the short and long term.
The
gene encodes the α-subunit of the voltage-gated cardiac sodium channel (Na
1.5), a key player in cardiac action potential depolarization. Genetic variants in protein-coding regions of the human
...have been largely associated with inherited cardiac arrhythmias. Increasing evidence also suggests that aberrant expression of the
gene could increase susceptibility to arrhythmogenic diseases, but the mechanisms governing
expression are not yet well understood. To gain insights into the molecular basis of
gene regulation, we used rat gastrocnemius muscle four days following denervation, a process well known to stimulate
expression. Our results show that denervation of rat skeletal muscle induces the expression of the adult cardiac
isoform. RNA-seq experiments reveal that denervation leads to significant changes in the transcriptome, with
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
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
in cardiac tissue is activated in response to denervation. Altogether, our experiments reveal that similar mechanisms regulate the expression of
in denervated muscle and cardiac tissue, suggesting a conserved pathway for
expression among striated muscles.
Selective neuronal loss is the hallmark of neurodegenerative diseases. In patients with amyotrophic lateral sclerosis (ALS), most motor neurons die but those innervating extraocular, pelvic ...sphincter, and slow limb muscles exhibit selective resistance. We identified 18 genes that show >10-fold differential expression between resistant and vulnerable motor neurons. One of these, matrix metalloproteinase-9 (MMP-9), is expressed only by fast motor neurons, which are selectively vulnerable. In ALS model mice expressing mutant superoxide dismutase (SOD1), reduction of MMP-9 function using gene ablation, viral gene therapy, or pharmacological inhibition significantly delayed muscle denervation. In the presence of mutant SOD1, MMP-9 expressed by fast motor neurons themselves enhances activation of ER stress and is sufficient to trigger axonal die-back. These findings define MMP-9 as a candidate therapeutic target for ALS. The molecular basis of neuronal diversity thus provides significant insights into mechanisms of selective vulnerability to neurodegeneration.
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
F-ASEM alpha7-nAChR targeting radiotracer as a new diagnostic method by visualizing skeletal muscle denervation in mouse models of sciatic nerve injury.
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,
F-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).
F-ASEM PET/MRI showed significantly increased
F-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
F-ASEM uptake in the denervated side when compared to the control (P = 0.0796).
Our results suggest that nAChR imaging with
F-ASEM has potential as a noninvasive diagnostic method for peripheral nervous system disorders.
The nerve transection model is an established and validated experimental model of skeletal muscle atrophy prepared by denervating the skeletal muscle in rodents. While a number of denervation ...techniques are available in rats, the development of various transgenic and knockout mice has also led to the wide use of mouse models of nerve transection. Skeletal muscle denervation experiments expand our knowledge of the physiological role of nerval activity and/or neurotrophic factors in the plasticity of skeletal muscle. The denervation of the sciatic or tibial nerve is a common experimental procedure in mice and rats, as these nerves can be resected without great difficulty. An increasing number of reports have recently been published on experiments using a tibial nerve transection technique in mice. In this chapter, we demonstrate and explain the procedures used to transect the sciatic and tibial nerves in mice.
Mutations in the MFN2 gene encoding Mitofusin 2 lead to the development of Charcot–Marie–Tooth type 2A (CMT2A), a dominant axonal form of peripheral neuropathy. Mitofusin 2 is localized at both the ...outer membrane of mitochondria and the endoplasmic reticulum and is particularly enriched at specialized contact regions known as mitochondria-associated membranes (MAM). We observed that expression of MFN2R94Q induces distal axonal degeneration in the absence of overt neuronal death. The presence of mutant protein leads to reduction in endoplasmic reticulum and mitochondria contacts in CMT2A patient-derived fibroblasts, in primary neurons and in vivo, in motoneurons of a mouse model of CMT2A. These changes are concomitant with endoplasmic reticulum stress, calcium handling defects, and changes in the geometry and axonal transport of mitochondria. Importantly, pharmacological treatments reinforcing endoplasmic reticulum–mitochondria cross-talk, or reducing endoplasmic reticulum stress, restore the mitochondria morphology and prevent axonal degeneration. These results highlight defects in MAM as a cellular mechanism contributing to CMT2A pathology mediated by mutated MFN2.
Aim
Symptoms of autonomic failure are frequently the presentation of advanced age and neurodegenerative diseases that impair adaptation to common physiologic stressors. The aim of this work was to ...examine the interaction between the sympathetic and motor nervous system, the involvement of the sympathetic nervous system (SNS) in neuromuscular junction (NMJ) presynaptic motor function, the stability of postsynaptic molecular organization, and the skeletal muscle composition and function.
Methods
Since muscle weakness is a symptom of diseases characterized by autonomic dysfunction, we studied the impact of regional sympathetic ablation on muscle motor innervation by using transcriptome analysis, retrograde tracing of the sympathetic outflow to the skeletal muscle, confocal and electron microscopy, NMJ transmission by electrophysiological methods, protein analysis, and state of the art microsurgical techniques, in C57BL6, MuRF1KO and Thy‐1 mice.
Results
We found that the SNS regulates motor nerve synaptic vesicle release, skeletal muscle transcriptome, muscle force generated by motor nerve activity, axonal neurofilament phosphorylation, myelin thickness, and myofibre subtype composition and CSA. The SNS also modulates the levels of postsynaptic membrane acetylcholine receptor by regulating the Gαi2‐Hdac4‐Myogenin‐MuRF1pathway, which is prevented by the overexpression of the guanine nucleotide‐binding protein Gαi2 (Q205L), a constitutively active mutant G protein subunit.
Conclusion
The SNS regulates NMJ transmission, maintains optimal Gαi2 expression, and prevents any increase in Hdac4, myogenin, MuRF1, and miR‐206. SNS ablation leads to upregulation of MuRF1, muscle atrophy, and downregulation of postsynaptic AChR. Our findings are relevant to clinical conditions characterized by progressive decline of sympathetic innervation, such as neurodegenerative diseases and aging.
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