Cardiac Sodium Channel Na<sub>v</sub>1.5 Arg222Gln Variant Induces a Sex-Specific Arrhythmia and Alters Mitochondrial Function
Bibliographic record
Abstract
Introduction: Encoded by the SCN5A gene, cardiac Nav1.5 sodium channels initiate the action potential to trigger a heartbeat. As the predominant sodium channel in the heart, variants can have devastating consequences, leading to potentially lethal arrhythmias. With the gain of function arginine to glutamine (Arg222Gln) variant in Nav1.5, patients develop intermittent arrhythmias and dilated cardiomyopathy. The stress induced by chronic arrhythmias can trigger adverse metabolic reprogramming, exacerbating the underlying condition. We have generated a murine model harboring the human Arg222Gln variant where we observe that only males produce a clear observable arrhythmia. We hypothesize that the maladaptive metabolic response to the arrhythmia caused by the Arg222Gln variant maybe be a potential link to the sex differences. Methods: The human exon containing the Arg222Gln mutation was knocked into a murine model under the endogenous SCN5A promoter. Cellular metabolism (oxygen consumption) was measured using primary adult mouse cardiomyocytes (CMs) with the Seahorse XFe analyzer. Mitochondrial membrane potential was measured using ratiometric JC-1 dye and imaged on a scanning confocal microscope. Heart tissues were diced into 1mm3 cubes and fixed to perform serial block face electron microscopy to obtain 3D structure of mitochondria and mitochondrial morphology. Western blots were used to detect protein levels. Results: Basal respiration of CMs were unchanged, however the maximal respiratory capacity of Arg222Gln males was significantly lower (116.9±13.5pmol O2/min, p<0.05) compared to WT males (407.3±16.4pmol O2/min). There were no differences between WT females (451.4±22.4pmol O2/min) and Arg222Gln females (463.2±33.7pmol O2/min). JC-1 dye revealed that the Arg222Gln males (0.6213±0.0172 red/green ratio, p<0.001) have significantly lowered mitochondrial polarization compared to WT males (0.7550 ±0.0257). There were no differences between WT females (0.6236±0.0154) and Arg222Gln females (0.6466±0.0139). Arg222Gln males have reduced mitochondria area (1.155±0.052μm2, p<0.05) compared to WT males (1.332±0.060μm2) and are more fragmented (p<0.05). Electron transport chain complex protein levels and mitochondrial biomass measured by voltage dependent anion channel protein levels remain unchanged between WT males and Arg222Gln males (P>0.05). The ratio of phosphorylated dynamin related (DRP) / total DRP protein levels were significantly higher in Arg222Gln males compared to WT males, indicative of mitochondrial fission (p<0.05). Conclusion: We demonstrate evidence of a mitochondrial dysfunction in a murine model of arrhythmia caused by a gain of function Nav1.5 variant, adversely affecting overall cellular metabolism and mitochondrial quality. Our data suggests that the difference in metabolic reprogramming could play a role in the cardioprotection against arrhythmia in Arg222Gln females or explain why Arg222Gln males are severely affected by the arrhythmia. Future experiments will aim to elucidate how the difference in sex affects cardiac metabolism in the context of Arg222Gln Nav1.5 variant. This work was supported by a Canadian Institutes of Health Research Project Grant, the SickKids Foundation through the Curtis Joseph and Harold Groves Chair in Anesthesia and Pain Medicine (JTM) and the Department of Anesthesiology and Pain Medicine, University of Toronto through a Merit Award (JTM). TYTL is supported by the CIHR Canadian Graduate Scholarship — Doctoral Award. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| Bibliometrics | 0.000 | 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) | 0.003 | 0.000 |
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".