Suetterlin, KJ;
Männikkö, R;
Matthews, E;
Greensmith, L;
Hanna, MG;
Bostock, H;
Tan, SV;
(2022)
Excitability properties of mouse and human skeletal muscle fibres compared by muscle velocity recovery cycles.
Neuromuscular Disorders
10.1016/j.nmd.2022.02.011.
(In press).
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Abstract
Mouse models of skeletal muscle channelopathies are not phenocopies of human disease. In some cases (e.g. Myotonia Congenita) the phenotype is much more severe, whilst in others (e.g. Hypokalaemic periodic paralysis) rodent physiology is protective. This suggests a species’ difference in muscle excitability properties. In humans these can be measured indirectly by the post-impulse changes in conduction velocity, using Muscle Velocity Recovery Cycles (MVRCs). We performed MVRCs in mice and compared their muscle excitability properties with humans. Mouse Tibialis Anterior MVRCs (n=70) have only one phase of supernormality (increased conduction velocity), which is smaller in magnitude (p=9 × 10−21), and shorter in duration (p=3 × 10−24) than human (n=26). This abbreviated supernormality is followed by a period of late subnormality (reduced velocity) in mice, which overlaps in time with the late supernormality seen in human MVRCs. The period of late subnormality suggests increased t-tubule Na+/K+-pump activity. The subnormal phase in mice was converted to supernormality by blocking chloride channels, suggesting relatively higher chloride conductance in mouse. Our findings help explain discrepancies in phenotype between mice and humans with skeletal muscle channelopathies and potentially other neuromuscular disorders. MVRCs are a valuable new tool to compare in vivo muscle membrane properties between species and will allow further dissection of the molecular mechanisms regulating muscle excitability.
| Type: | Article |
|---|---|
| Title: | Excitability properties of mouse and human skeletal muscle fibres compared by muscle velocity recovery cycles |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.nmd.2022.02.011 |
| Publisher version: | https://doi.org/10.1016/j.nmd.2022.02.011 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript, available under the Creative Commons Attribution Licence (CC BY 4.0) |
| Keywords: | Muscle Velocity Recovery Cycles (MVRCs); Excitability; ClC-1; Skeletal Muscle Channelopathies; Mouse modelTranslational gap |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10144834 |
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