Two Pathways Regulate Differential Expression of nAChRs Between the Orbicularis Oris and Gastrocnemius

Wu, Shuang; Huang, Yong; Xing, Yanfeng; Chen, Lianhua; Yang, Meirong; Li, Shitong

doi:10.1016/j.jss.2019.04.056

Cited by 3 publications

(7 citation statements)

References 42 publications

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“…NMJ remodeling and muscular atrophy are significant consequences of traumatic nerve injury ( 24 ). The NMJ normally assumes a pretzel-like morphology that is remodeled after injury ( 10 ). NMJ degradation may facilitate healthy motor nerve terminals to construct a new NMJ.…”

Section: Discussionmentioning

confidence: 99%

“…The NMJ normally has a pretzel-like morphology; however, this morphology is remodeled after facial nerve injury and the NMJ becomes fragile with an indistinct profile. Moreover, the nAChR is significantly upregulated at both synaptic and nonsynaptic sites in the orbicularis oris after facial nerve injury ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

“…The NMJ organizer agrin is secreted from motor neurons and has a major role in the formation and maintenance of NMJ ( 11 ). Neural agrin activates muscle-specific kinase (MuSK) tyrosine phosphorylation to promote nAChR aggregation at the NMJ ( 12 , 13 ); however, facial nerve injury can result in the downregulation of agrin, which decreases MuSK phosphorylation ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

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Inhibiting Matrix Metalloproteinases Protects Evoked Electromyography Amplitudes and Muscle Tension in the Orbicularis Oris Muscle in a Rat Model of Facial Nerve Injury

Song

et al. 2022

Journal of Neuropathology &Amp; Experimental Neurology

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Facial nerve injury results in degradation of the neuromuscular junction (NMJ) and blocks neurotransmission between the pre- and postsynaptic structures, which are separated by a synaptic cleft. Matrix metalloproteinases (MMPs), enzymes that degrade and modify the extracellular matrix, play critical roles in regulating NMJ remodeling. We previously demonstrated that MMP1, MMP2, MMP3, MMP7, and MMP9 are overexpressed in facial nerve-innervated orbicularis oris muscle after facial nerve injury in a rat model. In the present study, the MMP inhibitor prinomastat was administered to rats after facial nerve injury. The MMP levels, agrin expression, and muscle-specific kinase (MuSK) phosphorylation were evaluated. Variations in evoked electromyography (EEMG) amplitude were also recorded. Compared with the control group, MMP expression in the orbicularis oris after facial nerve injury was significantly reduced in the prinomastat group. Inhibition of MMP expression maintained agrin expression and MuSK phosphorylation; the NMJ morphology was also protected after the injury. Moreover, prinomastat treatment sustained EEMG amplitude and muscle tension after the injury. These findings indicate that inhibiting MMPs can protect the function and morphology of the NMJ and demonstrate the need for protection of the NMJ at early stages after facial nerve injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibiting Matrix Metalloproteinases Protects Evoked Electromyography Amplitudes and Muscle Tension in the Orbicularis Oris Muscle in a Rat Model of Facial Nerve Injury

Song

et al. 2022

Journal of Neuropathology &Amp; Experimental Neurology

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“…As reviewed by Kummer et al [44], a number of studies had implicated neuregulin-1 as having an important role, but two transgenic studies, in which synapses continued to form in the absence of either neuregulin-1′s receptors [48], or neuregulin-1 itself [49], essentially refuted this concept, although neuregulin-1 does play key roles in peripheral nervous system function, especially through actions on glia [50], as well as involvement in regulation of AChR synthesis [51,52]. With respect to agrin, however, many reports have simply ignored the findings that synapses can form in its absence.…”

Section: Synapse Formation: Two Mechanisms—agrin and Prepatterningmentioning

confidence: 99%

Nerve, Muscle, and Synaptogenesis

Swenarchuk

2019

Cells

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The vertebrate skeletal neuromuscular junction (NMJ) has long served as a model system for studying synapse structure, function, and development. Over the last several decades, a neuron-specific isoform of agrin, a heparan sulfate proteoglycan, has been identified as playing a central role in synapse formation at all vertebrate skeletal neuromuscular synapses. While agrin was initially postulated to be the inductive molecule that initiates synaptogenesis, this model has been modified in response to work showing that postsynaptic differentiation can develop in the absence of innervation, and that synapses can form in transgenic mice in which the agrin gene is ablated. In place of a unitary mechanism for neuromuscular synapse formation, studies in both mice and zebrafish have led to the proposal that two mechanisms mediate synaptogenesis, with some synapses being induced by nerve contact while others involve the incorporation of prepatterned postsynaptic structures. Moreover, the current model also proposes that agrin can serve two functions, to induce synaptogenesis and to stabilize new synapses, once these are formed. This review examines the evidence for these propositions, and concludes that it remains possible that a single molecular mechanism mediates synaptogenesis at all NMJs, and that agrin acts as a stabilizer, while its role as inducer is open to question. Moreover, if agrin does not act to initiate synaptogenesis, it follows that as yet uncharacterized molecular interactions are required to play this essential inductive role. Several alternatives to agrin for this function are suggested, including focal pericellular proteolysis and integrin signaling, but all require experimental validation.

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“…Upregulation of AChR expression could also result from activation of neuregulin1/ErbB signaling pathway through overexpression of MuSK and rapsyn (82). Whether this pathway is implicated in MG has not been documented.…”

Section: Molecular Changes and Mechanisms Of Compensationmentioning

confidence: 99%

The Muscle Is Not a Passive Target in Myasthenia Gravis

et al. 2019

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Myasthenia gravis (MG) is a rare autoimmune disease mediated by pathogenic antibodies (Ab) directed against components of the neuromuscular junction (NMJ), mainly the acetylcholine receptor (AChR). The etiological mechanisms are not totally elucidated, but they include a combination of genetic predisposition, triggering event(s), and hormonal components. MG disease is associated with defective immune regulation, chronic cell activation, inflammation, and the thymus is frequently abnormal. MG is characterized by muscle fatigability that is very invalidating and can be life-threatening when respiratory muscles are affected. MG is not cured, and symptomatic treatments with acetylcholinesterase inhibitors and immunosuppressors are lifelong medications associated with severe side effects (especially glucocorticoids). While the muscle is the ultimate target of the autoimmune attack, its place and role are not thoroughly described, and this mini-review will focus on the cascade of pathophysiologic mechanisms taking place at the NMJ and its consequences on the muscle biology, function, and regeneration in myasthenic patients, at the histological, cellular, and molecular levels. The fine structure of the synaptic cleft is damaged by the Ab binding that is coupled to focal complement-dependent lysis in the case of MG with anti-AChR antibodies. Cellular and molecular reactions taking place in the muscle involve several cell types as well as soluble factors. Finally, the regenerative capacities of the MG muscle tissue may be altered. Altogether, the studies reported in this review demonstrate that the muscle is not a passive target in MG, but interacts dynamically with its environment in several ways, activating mechanisms of compensation that limit the pathogenic mechanisms of the autoantibodies.

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Two Pathways Regulate Differential Expression of nAChRs Between the Orbicularis Oris and Gastrocnemius

Cited by 3 publications

References 42 publications

Inhibiting Matrix Metalloproteinases Protects Evoked Electromyography Amplitudes and Muscle Tension in the Orbicularis Oris Muscle in a Rat Model of Facial Nerve Injury

Inhibiting Matrix Metalloproteinases Protects Evoked Electromyography Amplitudes and Muscle Tension in the Orbicularis Oris Muscle in a Rat Model of Facial Nerve Injury

Nerve, Muscle, and Synaptogenesis

The Muscle Is Not a Passive Target in Myasthenia Gravis

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