Cardiomyocyte ATP Production, Metabolic Flexibility, and Survival Require Calcium Flux through Cardiac Ryanodine Receptors in Vivo
Bibliographic record
Abstract
Ca 2+ fluxes between adjacent organelles are thought to control many cellular processes, including metabolism and cell survival. In vitro evidence has been presented that constitutive Ca 2+ flux from intracellular stores into mitochondria is required for basal cellular metabolism, but these observations have not been made in vivo . We report that controlled in vivo depletion of cardiac RYR2, using a conditional gene knock-out strategy (c Ryr2 KO mice), is sufficient to reduce mitochondrial Ca 2+ and oxidative metabolism, and to establish a pseudohypoxic state with increased autophagy. Dramatic metabolic reprogramming was evident at the transcriptional level via Sirt1 / Foxo1 / Pgc1 α, Atf3 , and Klf15 gene networks. Ryr2 loss also induced a non-apoptotic form of programmed cell death associated with increased calpain-10 but not caspase-3 activation or endoplasmic reticulum stress. Remarkably, c Ryr2 KO mice rapidly exhibited many of the structural, metabolic, and molecular characteristics of heart failure at a time when RYR2 protein was reduced 50%, a similar degree to that which has been reported in heart failure. RYR2-mediated Ca 2+ fluxes are therefore proximal controllers of mitochondrial Ca 2+ , ATP levels, and a cascade of transcription factors controlling metabolism and survival. Background: Intracellular Ca 2+ release has been implicated in ATP production in vitro . Results: In vivo deletion of Ryr2 reduces Ca 2+ , ATP, and oxidative metabolism, leading to metabolic reprogramming and cell death. Conclusion: RYR2 maintains cardiomyocyte ATP production and survival in vivo . Significance: This work links heart metabolism to function via Ca 2+ release from intracellular stores.
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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".