Abstract P361: Reduced Cardiac Tmem65 In Mouse Hearts Results In Intercalated Disc Defects And Eventual Dilated Cardiomyopathy With Cardiac Fibrosis
Bibliographic record
Abstract
The intercalated disc (ICD) is unique membrane structure that is indispensable to normal heart function. However, its structural organization is not well understood. Previously, we showed that the ICD-bound transmembrane protein 65 (Tmem65) was required for connexin 43 (Cx43) localization 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 (or scrambled) shRNA. Quantitative polymerase chain reaction (qPCR) and immunoblots confirmed greater than 85% reduction in Tmem65 expression (7.1±0.7% remained for Tmem65 proteins; 14.4±2.5% remained for Tmem65 transcripts, n =4) in mouse ventricles compared to control hearts. Tmem65 knockdown (KD) mice exhibited heart failure-like symptoms as early as 3 weeks post viral administration. Specifically, Tmem65 KD mice developed eccentric hypertrophic cardiomyopathy in 3 weeks and dilated cardiomyopathy with severe cardiac fibrosis in 7 weeks, as confirmed by H&E and Masson’s Trichrome staining. Echocardiography and electrocardiography, respectively, showed depressed hemodynamics (19.27±1.46ml/min for cardiac output in control hearts vs. 6.63±0.52ml/min for Tmem65 KD hearts, n =6) and impaired conduction, including prolonged PR (22.7±1.85ms in control hearts vs. 28.89±3.85ms in Tmem65 KD hearts, n≥8), QRS intervals (10.47±0.42ms in control hearts vs. 16.35±0.36ms in Tmem65 KD hearts, n≥8), and slowed heart rate (415±10bpm in control hearts vs. 347±16bpm in Tmem65 KD hearts, n≥8) in Tmem65 KD mouse hearts. Immunoprecipitation and super-resolution microscopy confirmed the physical interaction and localization between Tmem65 and voltage-gated sodium channel β subunit (β1) at the ICD and this interaction was evidently required for the establishment of perinexal nanodomains and voltage-gated sodium channel 1.5 (NaV1.5) localization to the ICD. Disrupting Tmem65 function, thus, impaired perinexal structure, reduced conduction velocity, and ultimately resulted in cardiomyopathy in vivo .
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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 | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".