Diaphragm Assessment in Mice Overexpressing Phospholamban in Slow‐Twitch Type I Muscle Fibers
Bibliographic record
Abstract
Phospholamban (PLN) is a small transmembrane protein that regulates the sarco(endo)plasmic reticulum Ca 2+ ‐ATPase (SERCA) pump through direct physical interactions. Recent work published by our laboratory revealed that when PLN was transgenetically overexpressed in mice ( Pln OE ), the postural hind limb muscles presented a phenotype for human Centronuclear Myopathy (CNM). Specifically, Pln OE soleus and gluteus minimus muscles displayed: centrally located oxidative activity, a predominance of hypotrophied type I fibers, and an abundance of central nuclei. To further assess this novel model for CNM, we examined the diaphragm muscles of Pln OE mice, since studies assessing respiratory or diaphragm function in animal models of CNM were limited. Interestingly, our unpublished results suggest that unlike the soleus and gluteus minimus, diaphragm muscles did not display the main characteristics of CNM. Rather than exhibiting type I fiber predominance, the diaphragm muscles exhibited lower type I and greater type II fiber counts, which is of importance since the Pln OE mice were designed to overexpress PLN specifically in their type I fibers. Here, we sought to determine why the Pln OE diaphragm failed to exhibit type I fiber predominance similar to that seen in the soleus and gluteus minimus muscles. Specifically, we focused on calciuneurin (CnA), a Ca 2+ ‐dependent phosphatase, and its downstream effector target, nuclear factor of activating T‐cell (NFAT), that upon dephosphorylation by CnA, translocates to the nucleus and acts as a transcription factor for myosin heavy chain I (MHCI). We found that CnA content was significantly higher in both soleus (p=0.02) and gluteus minimus (p=0.05) muscles of Pln OE mice compared to wild type animals. Corresponding with this, nuclear NFAT levels were significantly increased in the gluteus minimus (p=0.01) and trending towards a significant increase in soleus muscle (p=0.07). In contrast, there were no differences between WT and Pln OE in CnA (p=0.23) or nuclear NFAT (p=0.42) content in diaphragm, which suggests the differences in fiber type transition and the CNM phenotype across muscles may be associated with the CnA‐NFAT pathway and calcium signaling. Together these data suggest that the diaphragm of the Pln OE mice may have some undetermined protective mechanism for better regulating cytosolic calcium levels and fiber type expression. Uncovering the mechanisms behind this resistance within the diaphragm of PLN OE mice may aid in exploring new therapeutic strategies for CNM.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".