Geranylgeraniol Prevents Statin‐Dependent Myotoxicity in C2C12 Muscle Cells through RAP1 GTPase Prenylation and Cytoprotective Autophagy
Bibliographic record
Abstract
The present study investigated the cytotoxic effects of statins (atorvastatin (ATR) and simvastatin (SIM), resp.) and methyl‐beta‐cyclodextrin (M β CD), at their respective IC 50 concentrations, on muscle regeneration in the in vitro model of murine C2C12 myoblasts. Cotreatment with mevalonate (MEV), farnesol (FOH), geranylgeraniol (GGOH), or water‐soluble cholesterol (Chol‐PEG) was employed to determine whether the statin‐dependent myotoxicity resulted from the lower cholesterol levels or the attenuated synthesis of intermediates of mevalonate pathway. Our findings demonstrated that while GGOH fully reverted the statin‐mediated cell viability in proliferating myoblasts, Chol‐PEG exclusively rescued M β CD‐induced toxicity in myocytes. Statins caused loss of prenylated RAP1, whereas the GGOH‐dependent positive effect was accompanied by loss of nonprenylated RAP1. Geranylgeranyltransferases are essential for muscle cell survival as inhibition with GGTI‐286 could not be reversed by GGOH cotreatment. The increase in cell viability correlated with elevated AKT 1(S463) and GSK‐3 β (S9) phosphorylations. Slight increase in the levels of autophagy markers (Beclin 1, MAP LC‐3IIb) was found in response to GGOH cotreatment. Autophagy rose time‐dependently during myogenesis and was inhibited by statins and M β CD. Statins and M β CD also suppressed myogenesis and neither nonsterol isoprenoids nor Chol‐PEG could reverse this effect. These results point to GGOH as the principal target of statin‐dependent myotoxicity, whereas plasma membrane cholesterol deposit is ultimately essential to restore viability of M β CD‐treated myocytes. Overall, this study unveils for the first time a link found between the GGOH‐ and Chol‐PEG‐dependent reversal of statin‐ or M β CD‐mediated myotoxicity and cytoprotective autophagy, respectively.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 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 teacher head, 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".