Molecular rewiring of human induced pluripotent stem cell-derived cardiomyocytes during metabolic maturation
Bibliographic record
Abstract
Abstract Human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) are widely used to model cardiac development and inherited cardiomyopathies, yet their immature metabolic state limits interpretation of disease-associated molecular programs. While multiple strategies promote structural and functional maturation, less is known about the molecular regulation of metabolic maturation as a distinct developmental transition. Here, we examine how metabolic maturation reshapes molecular and metabolic states in wild-type and TNNT2 -linked hypertrophic cardiomyopathy (HCM) hiPSC-CMs. Using integrated transcriptomic, chromatin accessibility, proteomic, and metabolic profiling, we define the molecular trajectory associated with metabolic maturation in wild-type hiPSC-CMs, characterized by coordinated transcriptional and epigenetic remodeling, enhanced mitochondrial oxidative metabolism, and progressive suppression of mTORC1 signaling. In contrast, hiPSC-CMs carrying TNNT2 HCM variants (I79N +/− and R278C +/− ) exhibit variant-specific deviations from this metabolic maturation trajectory. While early CM differentiation is largely preserved, metabolic maturation reveals defects in mitochondrial respiration and chromatin organization, with the more clinically severe I79N +/− variant showing sustained metabolic impairment. We further find that mTORC1 activity is temporally misregulated during metabolic maturation in HCM hiPSC-CMs, with reduced signaling at early stages and normalization at later time points. Pharmacological inhibition of mTORC1 with rapamycin partially improves disease-associated protein expression signatures in the I79N +/− variant, particularly when applied during early differentiation. Together, these findings demonstrate that TNNT2-linked HCM involves disrupted metabolic maturation programs coupled to altered gene regulatory states, highlighting metabolic maturation as a critical context for studying cardiomyopathy-associated molecular phenotypes in hiPSC-CMs.
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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) | 0.000 | 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) | 0.001 | 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".