Acute Severe Animal Model of Anti–Muscle-Specific Kinase Myasthenia

Richman, David P.; Nishi, Kayoko; Morell, Stuart W.; Chang, Jolene Mi; Ferns, Michael J.; Wollmann, Robert L.; Maselli, Ricardo A.; Schnier, Joachim; Agius, Mark

doi:10.1001/archneurol.2011.2200

Cited by 28 publications

(6 citation statements)

References 43 publications

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“…These data, together with the co‐immunoprecipitation data, strongly indicate that cTnT at the NMJ contributes to PKA RIIα enrichment at NMJ in old TA muscle, which may competitively reduce PKA RIα at NMJ. Consequently, TA muscle with cTnT knocked down showed increased amplitude of CMAPs ( Figure 8), which is a crucial in vivo method to determine neuromuscular transmission efficiency 21, 24, 25. Altogether, our data suggest that down‐regulation of cTnT at the NMJ may displace PKA RIIα from the NMJ and rescue RIα enrichment at that site, leading to enhanced NMJ function in muscle in vivo .…”

Section: Resultsmentioning

confidence: 69%

Cardiac troponin T and fast skeletal muscle denervation in ageing

Feng

Dong

et al. 2017

J cachexia sarcopenia muscle

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BackgroundAgeing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast‐twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow‐twitch fibres. However, how this process is regulated is largely unknown. A better understanding of the mechanisms regulating skeletal muscle fibre‐type specific denervation at the NMJ could be critical to identifying novel treatments for sarcopenia. Cardiac troponin T (cTnT), the heart muscle‐specific isoform of TnT, is a key component of the mechanisms of muscle contraction. It is expressed in skeletal muscle during early development, after acute sciatic nerve denervation, in various neuromuscular diseases and possibly in ageing muscle. Yet the subcellular localization and function of cTnT in skeletal muscle is largely unknown.MethodsStudies were carried out on isolated skeletal muscles from mice, vervet monkeys, and humans. Immunoblotting, immunoprecipitation, and mass spectrometry were used to analyse protein expression, real‐time reverse transcription polymerase chain reaction was used to measure gene expression, immunofluorescence staining was performed for subcellular distribution assay of proteins, and electromyographic recording was used to analyse neurotransmission at the NMJ.ResultsLevels of cTnT expression in skeletal muscle increased with ageing in mice. In addition, cTnT was highly enriched at the NMJ region—but mainly in the fast‐twitch, not the slow‐twitch, muscle of old mice. We further found that the protein kinase A (PKA) RIα subunit was largely removed from, while PKA RIIα and RIIβ are enriched at, the NMJ—again, preferentially in fast‐twitch but not slow‐twitch muscle in old mice. Knocking down cTnT in fast skeletal muscle of old mice: (i) increased PKA RIα and reduced PKA RIIα at the NMJ; (ii) decreased the levels of gene expression of muscle denervation markers; and (iii) enhanced neurotransmission efficiency at NMJ.ConclusionsCardiac troponin T at the NMJ region contributes to NMJ functional decline with ageing mainly in the fast‐twitch skeletal muscle through interfering with PKA signalling. This knowledge could inform useful targets for prevention and therapy of age‐related decline in muscle function.

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Section: Resultsmentioning

confidence: 69%

Cardiac troponin T and fast skeletal muscle denervation in ageing

Feng

Dong

et al. 2017

J cachexia sarcopenia muscle

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“…A fragmented and reduced AChR area at NMJs is a well-described pathological feature, causing muscle weakness in MuSK MG animal models ( 10 , 17 , 18 , 20 , 34 – 37 ). To investigate the postsynaptic NMJ morphology after in vivo exposure to mono- and bivalent MuSK antibodies, AChRs were stained in whole-mount preparations of the right hemidiaphragm and epitrochleoanconeus (ETA) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis

Vergoossen

Plomp

Gstöttner

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Human immunoglobulin (Ig) G4 usually displays antiinflammatory activity, and observations of IgG4 autoantibodies causing severe autoimmune disorders are therefore poorly understood. In blood, IgG4 naturally engages in a stochastic process termed “Fab-arm exchange” in which unrelated IgG4s exchange half-molecules continuously. The resulting IgG4 antibodies are composed of two different binding sites, thereby acquiring monovalent binding and inability to cross-link for each antigen recognized. Here, we demonstrate that this process amplifies autoantibody pathogenicity in a classic IgG4-mediated autoimmune disease: muscle-specific kinase (MuSK) myasthenia gravis. In mice, monovalent anti-MuSK IgG4s caused rapid and severe myasthenic muscle weakness, whereas the same antibodies in their parental bivalent form were less potent or did not induce a phenotype. Mechanistically this could be explained by opposing effects on MuSK signaling. Isotype switching to IgG4 in an autoimmune response thereby may be a critical step in the development of disease. Our study establishes functional monovalency as a pathogenic mechanism in IgG4-mediated autoimmune disease and potentially other disorders.

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“…Animal models have revealed other abnormalities of the NMJ during MuSK-MG [31] – [34] , [47] . Mori et al [32] observed a decline of quantal content, while others observed that quantal content remains normal for MuSK-MG mice [33] , [34] , [49] , although these latter studies report other abnormalities of nerve function.…”

Section: Discussionmentioning

confidence: 99%

Altered Active Zones, Vesicle Pools, Nerve Terminal Conductivity, and Morphology during Experimental MuSK Myasthenia Gravis

Patel

Voit

et al. 2014

PLoS ONE

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Recent studies demonstrate reduced motor-nerve function during autoimmune muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG). To further understand the basis of motor-nerve dysfunction during MuSK-MG, we immunized female C57/B6 mice with purified rat MuSK ectodomain. Nerve-muscle preparations were dissected and neuromuscular junctions (NMJs) studied electrophysiologically, morphologically, and biochemically. While all mice produced antibodies to MuSK, only 40% developed respiratory muscle weakness. In vitro study of respiratory nerve-muscle preparations isolated from these affected mice revealed that 78% of NMJs produced endplate currents (EPCs) with significantly reduced quantal content, although potentiation and depression at 50 Hz remained qualitatively normal. EPC and mEPC amplitude variability indicated significantly reduced number of vesicle-release sites (active zones) and reduced probability of vesicle release. The readily releasable vesicle pool size and the frequency of large amplitude mEPCs also declined. The remaining NMJs had intermittent (4%) or complete (18%) failure of neurotransmitter release in response to 50 Hz nerve stimulation, presumably due to blocked action potential entry into the nerve terminal, which may arise from nerve terminal swelling and thinning. Since MuSK-MG-affected muscles do not express the AChR γ subunit, the observed prolongation of EPC decay time was not due to inactivity-induced expression of embryonic acetylcholine receptor, but rather to reduced catalytic activity of acetylcholinesterase. Muscle protein levels of MuSK did not change. These findings provide novel insight into the pathophysiology of autoimmune MuSK-MG.

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Acute Severe Animal Model of Anti–Muscle-Specific Kinase Myasthenia

Cited by 28 publications

References 43 publications

Cardiac troponin T and fast skeletal muscle denervation in ageing

Cardiac troponin T and fast skeletal muscle denervation in ageing

Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis

Altered Active Zones, Vesicle Pools, Nerve Terminal Conductivity, and Morphology during Experimental MuSK Myasthenia Gravis

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