Sarcolipin Deletion in <i>mdx</i> Mice Worsens Dystrophic Pathology by Impairing Calcineurin Signaling and Reducing Utrophin Expression
Bibliographic record
Abstract
Duchenne's muscular dystrophy (DMD) is the most severe form of muscular dystrophy affecting 1 in 3500 live male births. There is no cure for DMD and males typically succumb to early mortality induced by respiratory and cardiac insufficiency. Thus, finding viable therapeutic targets is of utmost importance. Sarcolipin (SLN), a sarco(endo)plasmic reticulum Ca 2+ ‐ATPase (SERCA) pump inhibitor, is highly upregulated in dystrophic muscles from mdx mice, a mouse model for DMD. To date, the role of SLN in muscular dystrophy remains unknown, and therefore, in this study we crossed Sln KO mice with mdx mice to generate the mdx / Sln KO double knockout mutant mouse. We hypothesized that Sln deletion would worsen dystrophic myopathy based on unpublished results from our laboratory and previous studies showing that SLN can stimulate calcineurin – a Ca 2+ ‐dependent serine/threonine phosphatase shown to counteract muscular dystrophy. Our findings show that mdx / Sln KO myofibers from soleus ( P = 0.0001) and diaphragm ( P < 0.0001) were significantly smaller than those from mdx . Furthermore, mdx / Sln KO soleus and diaphragm muscles displayed a slow‐to‐fast fiber type shift, which was associated with a significant reduction in utrophin ( P = 0.004). Utrophin, a dystrophin homolog that confers compensatory membrane stability, is largely controlled by calcineurin, suggesting that SLN in mdx mice stimulates calcineurin signaling. In addition, the significant reductions in utrophin expression in the mdx / Sln KO mice can account for their worsened dystrophic pathology revealed by greater serum creatine kinase ( P = 0.01) and greater variability in myofiber size (minimal Feret's diameter, P = 0.01) compared with mdx . Finally, lower central nuclei counts in muscles from mdx / Sln KO mice compared with mdx ( P = 0.04) suggests that genetic deletion of Sln also potentially impairs the muscles’ regenerative capacity. Taken together, these results, for the first time clearly demonstrate SLN's vital role in countering muscular dystrophy. Support or Funding Information This work was supported by the Canadian Institutes of Health Research (CIHR; MOP 86618 and MOP 47296 to A.R.T).
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".