Characterizing the effects of heterozygous neurogranin deletion on myosin heavy chain and calcineurin expression in the murine unloaded soleus
Bibliographic record
Abstract
Background Neurogranin (Ng) is a small IQ motif protein that binds to the C‐terminal on CaM limiting its cellular availability and sequestering it away from its downstream targets such as calcineurin. Calcineurin is a Ca 2+ /calmodulin (CaM)‐dependent protein that promotes the slow oxidative fibre phenotype in skeletal muscle as well as myoblast fusion. Recent research from our lab shows that Ng is expressed in skeletal muscle, particularly in slow‐oxidative muscles such as the soleus. The soleus is a postural muscle that acts to withstand the downward pull of gravity and unloading the soleus muscle leads to muscle atrophy and a slow‐to‐fast fibre type shift. However, activating calcineurin can attenuate the muscle atrophy and fibre type transition that occurs with soleus unloading. In the present study, we determined the effects of heterozygous Ng deletion on muscle mass and myosin heavy chain (MHC) isoform expression in the unloaded soleus. We hypothesized that lowered Ng expression would enhance calcineurin signaling thereby minimizing muscle atrophy and the slow‐to‐fast fibre type shift. Methods To this end, 3‐4 month‐old male wild‐type (WT) (n=6) and Ng +/‐ (n=8) mice were subjected to tenotomy surgery, where the soleus and gastrocnemius tendons were severed. Soleus muscles were collected two weeks post‐surgery for Western blotting to examine differences in MHC I, IIa, and calcineurin content. Results Soleus to bodyweight ratio was significantly reduced in the unloaded/tenotomy group for both WT (‐55%) and Ng +/‐ mice (‐51%) compared with their respective sham controls ( p <0.001). Western blot analyses revealed that tenotomy‐induced unloading significantly lowered MHC I (‐60%, p =0.03) and MHC IIa (‐63%, p= 0.0001) content, while increasing calcineurin levels (1.4‐fold, p =0.003). However, these effects were blunted in the Ng +/‐ mice with only a 43% reduction in MHC I ( p =0.01), 40% reduction in MHC IIa ( p =0.01), and a non‐significant change in calcineurin (1.0‐fold, p =0.98). Two‐way ANOVA analyses revealed a significant interaction (genotype x tenotomy) for MHC IIa ( p =0.01) and calcineurin ( p =0.007) inidicating that WT mice were more impacted by tenotomy‐induced soleus unloading. Conclusions Our results show that heterozygous Ng deletion did not reduce the muscle atrophy observed with soleus unloading. However, with respect to MHC isoform expression, Ng +/‐ mice were less impacted by unloading with only 40‐43% reductions in MHC I and IIa. This could suggest a blunted slow‐to‐fast fibre type shift. Interestingly, calcineurin was significantly upregulated in the unloaded WT soleus, which we believe is a compensatory response elicited to combat the effects of tenotomy. However, this response was completely absent in the Ng +/‐ mice, perhaps due to sufficient activation of calcineurin with lowered Ng content. In conclusion, this study shows that Ng +/‐ mice respond differently to soleus unloading compared with WT mice.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".