Targeted single point mutation of NaV1.4 in mouse increases sodium influx and potassium‐induced force depression in EDL and soleus muscle
Bibliographic record
Abstract
The single point mutation M1592V on the human skeletal muscle sodium channel, NaV1.4, causes Hyperkalemic Periodic Paralysis (HyperKPP). HyperKPP is associated with greater sodium influx and sensitivity to the potassium depressing effect on force. The objective of this study was to determine if introducing a missense substitution corresponding to a human familial HyperKPP mutation (Met1592Val) into the mouse gene (mice (+/M1592V) ) encoding the skeletal muscle voltage‐gated Na+ channel NaV1.4 also results in greater sodium flux and potassium sensitivity. EDL and soleus muscles were exposed to either 4.7 mM (control) or 9–10 mM K + while measuring either 22 Na + uptake or peak tetanic force. 22 Na + uptake was 3‐times greater in EDL and soleus muscles of mice (+/M1592V) when compared to the uptake in wild type muscles. The drop in peak tetanic force at 9–10 mM was much greater in EDL and soleus muscles of mice (+/M1592V) than in wild type muscles. Furthermore, adding 1–2 nM TTX, to partially block sodium channels, caused a decrease in peak tetanic force in wild type muscles but produced an increase in force in EDL and soleus muscles of mice (+/M1592V) . However, the peak tetanic force of muscle (+/M1592V) in the presence of TTX was still less than that observed in wild type muscles. We conclude that the introduction of the M1592V mutation in the mouse genome increases sodium influx and the K + sensitivity of skeletal muscle as observed in human suffering of HyperKPP. However, partially blocking Na + channels with TTX failed to return the force back to the level observed in wild type muscles, which suggests that an increased intracellular sodium also contributes to the reduced force.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".