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Change of voltage‐gated sodium channel repertoire in skeletal muscle of a MuSK myasthenia gravis mouse model.

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Title: Change of voltage‐gated sodium channel repertoire in skeletal muscle of a MuSK myasthenia gravis mouse model.
Authors: Butenko, Olena (AUTHOR), Jensen, Stine Marie (AUTHOR), Fillié‐Grijpma, Yvonne E. (AUTHOR), Verpalen, Robyn (AUTHOR), Verschuuren, Jan J. (AUTHOR), van der Maarel, Silvère M. (AUTHOR), Huijbers, Maartje G. (AUTHOR), Plomp, Jaap J. (AUTHOR)
Source: European Journal of Neuroscience. Jun2024, Vol. 59 Issue 12, p3292-3308. 17p.
Subjects: Sodium channels, Action potentials, Laboratory mice, Muscle weakness, Animal disease models, Myasthenia gravis, Skeletal muscle
Abstract: Muscle‐specific kinase myasthenia gravis (MuSK MG) is caused by autoantibodies against MuSK in the neuromuscular junction (NMJ). MuSK MG patients have fluctuating, fatigable skeletal muscle weakness, in particular of bulbar muscles. Severity differs greatly between patients, in spite of comparable autoantibody levels. One explanation for inter‐patient and inter‐muscle variability in sensitivity might be variations in compensatory muscle responses. Previously, we developed a passive transfer mouse model for MuSK MG. In preliminary ex vivo experiments, we observed that muscle contraction of some mice, in particular those with milder myasthenia, had become partially insensitive to inhibition by μ‐Conotoxin‐GIIIB, a blocker of skeletal muscle NaV1.4 voltage‐gated sodium channels. We hypothesised that changes in NaV channel expression profile, possibly co‐expression of (μ‐Conotoxin‐GIIIB insensitive) NaV1.5 type channels, might lower the muscle fibre's firing threshold and facilitate neuromuscular synaptic transmission. To test this hypothesis, we here performed passive transfer in immuno‐compromised mice, using 'high', 'intermediate' and 'low' dosing regimens of purified MuSK MG patient IgG4. We compared myasthenia levels, μ‐Conotoxin‐GIIIB resistance and muscle fibre action potential characteristics and firing thresholds. High‐ and intermediate‐dosed mice showed clear, progressive myasthenia, not seen in low‐dosed animals. However, diaphragm NMJ electrophysiology demonstrated almost equal myasthenic severities amongst all regimens. Nonetheless, low‐dosed mouse diaphragms showed a much higher degree of μ‐Conotoxin‐GIIIB resistance. This was not explained by upregulation of Scn5a (the NaV1.5 gene), lowered muscle fibre firing thresholds or histologically detectable upregulated NaV1.5 channels. It remains to be established which factors are responsible for the observed μ‐Conotoxin‐GIIIB insensitivity and whether the NaV repertoire change is compensatory beneficial or a bystander effect. [ABSTRACT FROM AUTHOR]
Copyright of European Journal of Neuroscience is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Label: Title
  Group: Ti
  Data: Change of voltage‐gated sodium channel repertoire in skeletal muscle of a MuSK myasthenia gravis mouse model.
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  Data: <searchLink fieldCode="AR" term="%22Butenko%2C+Olena%22">Butenko, Olena</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Jensen%2C+Stine+Marie%22">Jensen, Stine Marie</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Fillié‐Grijpma%2C+Yvonne+E%2E%22">Fillié‐Grijpma, Yvonne E.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Verpalen%2C+Robyn%22">Verpalen, Robyn</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Verschuuren%2C+Jan+J%2E%22">Verschuuren, Jan J.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22van+der+Maarel%2C+Silvère+M%2E%22">van der Maarel, Silvère M.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Huijbers%2C+Maartje+G%2E%22">Huijbers, Maartje G.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Plomp%2C+Jaap+J%2E%22">Plomp, Jaap J.</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22European+Journal+of+Neuroscience%22">European Journal of Neuroscience</searchLink>. Jun2024, Vol. 59 Issue 12, p3292-3308. 17p.
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  Data: <searchLink fieldCode="DE" term="%22Sodium+channels%22">Sodium channels</searchLink><br /><searchLink fieldCode="DE" term="%22Action+potentials%22">Action potentials</searchLink><br /><searchLink fieldCode="DE" term="%22Laboratory+mice%22">Laboratory mice</searchLink><br /><searchLink fieldCode="DE" term="%22Muscle+weakness%22">Muscle weakness</searchLink><br /><searchLink fieldCode="DE" term="%22Animal+disease+models%22">Animal disease models</searchLink><br /><searchLink fieldCode="DE" term="%22Myasthenia+gravis%22">Myasthenia gravis</searchLink><br /><searchLink fieldCode="DE" term="%22Skeletal+muscle%22">Skeletal muscle</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Muscle‐specific kinase myasthenia gravis (MuSK MG) is caused by autoantibodies against MuSK in the neuromuscular junction (NMJ). MuSK MG patients have fluctuating, fatigable skeletal muscle weakness, in particular of bulbar muscles. Severity differs greatly between patients, in spite of comparable autoantibody levels. One explanation for inter‐patient and inter‐muscle variability in sensitivity might be variations in compensatory muscle responses. Previously, we developed a passive transfer mouse model for MuSK MG. In preliminary ex vivo experiments, we observed that muscle contraction of some mice, in particular those with milder myasthenia, had become partially insensitive to inhibition by μ‐Conotoxin‐GIIIB, a blocker of skeletal muscle NaV1.4 voltage‐gated sodium channels. We hypothesised that changes in NaV channel expression profile, possibly co‐expression of (μ‐Conotoxin‐GIIIB insensitive) NaV1.5 type channels, might lower the muscle fibre's firing threshold and facilitate neuromuscular synaptic transmission. To test this hypothesis, we here performed passive transfer in immuno‐compromised mice, using 'high', 'intermediate' and 'low' dosing regimens of purified MuSK MG patient IgG4. We compared myasthenia levels, μ‐Conotoxin‐GIIIB resistance and muscle fibre action potential characteristics and firing thresholds. High‐ and intermediate‐dosed mice showed clear, progressive myasthenia, not seen in low‐dosed animals. However, diaphragm NMJ electrophysiology demonstrated almost equal myasthenic severities amongst all regimens. Nonetheless, low‐dosed mouse diaphragms showed a much higher degree of μ‐Conotoxin‐GIIIB resistance. This was not explained by upregulation of Scn5a (the NaV1.5 gene), lowered muscle fibre firing thresholds or histologically detectable upregulated NaV1.5 channels. It remains to be established which factors are responsible for the observed μ‐Conotoxin‐GIIIB insensitivity and whether the NaV repertoire change is compensatory beneficial or a bystander effect. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of European Journal of Neuroscience is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.1111/ejn.16347
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 17
        StartPage: 3292
    Subjects:
      – SubjectFull: Sodium channels
        Type: general
      – SubjectFull: Action potentials
        Type: general
      – SubjectFull: Laboratory mice
        Type: general
      – SubjectFull: Muscle weakness
        Type: general
      – SubjectFull: Animal disease models
        Type: general
      – SubjectFull: Myasthenia gravis
        Type: general
      – SubjectFull: Skeletal muscle
        Type: general
    Titles:
      – TitleFull: Change of voltage‐gated sodium channel repertoire in skeletal muscle of a MuSK myasthenia gravis mouse model.
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            NameFull: Butenko, Olena
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            – D: 15
              M: 06
              Text: Jun2024
              Type: published
              Y: 2024
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