Abstract P2018: Tmem65 Is Critical For The Structure And Function Of The Intercalated Discs In Mouse Hearts
Bibliographic record
Abstract
The intercalated disc (ICD) is unique membrane structure that is indispensable to normal heart function, yet its structural organization is not completely understood. Previously, we showed that the ICD-bound transmembrane protein 65 (Tmem65) was required for connexin 43 (Cx43) localization and function in cultured mouse neonatal cardiomyocytes. Here, we investigated the role of Tmem65 in ICD organization in vivo . A mouse model was established by injecting CD1 mouse pups (3-7 days after birth) with recombinant adeno-associated virus 9 (rAAV9) harboring Tmem65 shRNA which resulted in a 90% reduction of Tmem65 expression in mouse ventricles compared to mice injected with scrambled shRNA. Tmem65 knockdown (KD) resulted in increased mortality which was accompanied by eccentric hypertrophic cardiomyopathy within 3 weeks of injection, progressing to dilated cardiomyopathy with severe cardiac fibrosis by 7 weeks post-injection. Tmem65 KD hearts displayed depressed hemodynamics, measured echocardiographically, accompanied by electrocardiogram changes (prolonged PR intervals and QRS duration) consistent with impaired conduction, which was confirmed with optical mapping of isolated hearts. Immunoprecipitation and super-resolution microscopy demonstrated a physical interaction between Tmem65 and sodium channel β subunit (β1) in mouse hearts and this interaction appeared to be required for both the establishment of perinexal nanodomain structure and the localization of both voltage-gated sodium channel 1.5 (NaV1.5) and Cx43 to ICDs. Despite the loss of NaV1.5 at the ICDs, whole-cell patch clamp electrophysiology did not reveal reductions in Na + currents but did show reduced Ca 2+ and K + currents in Tmem65 KD cardiomyocytes in comparison to control cells. We conclude that disrupting Tmem65 function results in impaired ICD structure, abnormal cardiac electrophysiology, and ultimately cardiomyopathy.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".