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Publication Detail
Differences in Muscle Phenotype Severity between Humans and Mice with Monogenic Disorders may help Identify Novel Therapeutic Pathways
  • Publication Type:
    Conference presentation
  • Authors:
    Suetterlin K, Bostock H, Mannikko R, Dick J, Matthews E, Greensmith L, Hanna M, Tan SV
  • Date:
    04/04/2019
  • Name of Conference:
    12th UK Neuromuscular Translational Conference
  • Conference place:
    Newcastle
  • Conference start date:
    04/04/2019
  • Conference finish date:
    05/04/2019
  • Keywords:
    translation, mouse model, periodic paralysis, skeletal muscle excitability, ion channel function
Abstract
Background: The four transgenic mouse models of periodic paralysis recapitulate many features of the human disease. They have similar pathology, the same gender difference in phenotype severity and muscle weakness is consistently induced on exposure to extremes of potassium. However, none of the mouse models have ever been observed to have a spontaneous attack of weakness and the potassium concentration needed to induce an attack is more extreme than that reported for humans. Aims: 1. To identify differences in normal mouse and human muscle excitability and explore these differences using selective pharmacological blockade. 2. To test whether the identified differences protect against spontaneous attacks of weakness in mice with periodic paralysis. Methods: Muscle velocity recovery cycles (MVRCs) can be used to indirectly measure muscle excitability in vivo. In human muscle there are two phases of increased conduction velocity. The first, known as early supernormality, has a correlate in nerve and reflects passive decay of charge that has accumulated in the sarcolemma. The second, known as late supernormality, is specific to muscle and reflects activity-induced potassium accumulation in the t-tubules. MVRCs have not previously been reported in mice. MVRCs were recorded under anaesthesia in Wild-type C57BlJ6 mouse Tibialis Anterior (TA), using QTRAC software, as described for humans. Intraperitoneal injection of 9-Anthracene-carboxylic-acid was used to block ClC-1 channels and micromolar ouabain to selectively block the t-tubule Na/K pump. MVRCs were recorded pre- and post-pharmacology in the same animal. Results: In contrast to human MVRCs, mouse MVRCs had no late supernormality. Blockade of ClC-1 induced late supernormality in mouse TA (p=0.002, t-test with Welch correction). Blockade of the t-tubule Na/K pump induced late supernormality in 3 of 14 TAs exposed to ouabain compared to 0 of 66 not exposed to ouabain (p= 0.007, two-tailed Fisher exact test). Conclusions MVRCs can be recorded in mice. Our data suggest that, compared to humans, mice have more effective t-tubule potassium buffering and clearance. This is due, at least in part, to an increased ClC-1 conductance and t-tubule Na/K pump activity. The next step will be to determine if this protects against spontaneous attacks of weakness in mice with periodic paralysis.
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Department of Neuromuscular Diseases
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Department of Neuromuscular Diseases
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Department of Neuromuscular Diseases
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Department of Neuromuscular Diseases
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Department of Neuromuscular Diseases
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Department of Neuromuscular Diseases
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