Myocardin Regulated Genetic Pathway Modulates Mitochondrial Permeability Transition Pore Closure to Prevent Cell Death during Cardiac Differentiation
Bibliographic record
Abstract
Myocardin is a transcriptional co‐activator required for cardiovascular development and cardiomyocyte differentiation. Recent studies have shown that genetic inhibition of myocardin results in congenital heart defects associated with increased programmed cell death (PCD). In addition to its established role in regulating PCD, the mitochondrial permeability transition pore (PTP) has been implicated in cardiac calcium homeostasis and myocyte maturation during development. Utilizing fluorescent staining and biochemical assays, we demonstrate that myocardin, a modulator of cardiac gene function, regulates mitochondrial PTP closure during myocyte differentiation to oppose pathways of PCD induced by protein kinase‐A (PKA) activating agents. We show that a loss of myocardin function reduces microRNA‐133a (miR‐133a) mRNA levels and induces mitochondrial dysfunction by PTP opening and reducing mitochondrial membrane potential. Furthermore, myocardin knockdown increased mitochondrial oxidative stress and mitochondrial calcium uptake in differentiated myocytes. Conversely, restoring myocardin expression rescued mitochondrial function, concurrent with a decreased expression of a mitochondrial death protein, Nix. Furthermore, miR‐133a protects against PKA‐activating agents while inhibitory molecules opposing miR‐133a increase Nix expression. With the use of genetically encoded and organelle targeted calcium sensors, our data demonstrates that miR‐133a reverses endoplasmic reticulum calcium release and prevents mitochondrial calcium uptake, in a manner dependent on Nix repression. Finally, we provide mechanistic evidence that myocardin‐dependent miR‐133a expression is regulated by histone deactylase‐5 (HDAC5) and the PKA‐regulated salt inducible kinase‐1 (SIK1). These findings support the notion that myocardin opposes PCD through mitochondrial permeability transition by regulating calcium homeostasis; however, this genetic pathway may be attenuated by pathological PKA signaling. Support or Funding Information Supported by Children's Hospital Foundation of Manitoba, Research Manitoba and NSERC Canada.
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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 | 0.001 |
| 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".