Statin administration activates system xC <sup>−</sup> in skeletal muscle: a potential mechanism explaining statin-induced muscle pain
Bibliographic record
Abstract
Statins are a cholesterol-lowering drug class that significantly reduce cardiovascular disease risk. Despite their safety and effectiveness, musculoskeletal side-effects, particularly myalgia, are prominent and the most common reason for discontinuance. The cause of statin-induced myalgia is unknown, so defining the underlying mechanism(s) and potential therapeutic strategies is of clinical importance. Here we tested the hypothesis that statin administration activates skeletal muscle system xC − , a cystine/glutamate antiporter, to increase intracellular cysteine and therefore glutathione synthesis to attenuate statin-induced oxidative stress. Increased system xC − activity would increase interstitial glutamate; an amino acid associated with peripheral nociception. Consistent with our hypothesis, atorvastatin treatment significantly increased mitochondrial reactive oxygen species (ROS; 41%) and glutamate efflux (up to 122%) in C2C12 mouse skeletal muscle myotubes. Statin-induced glutamate efflux was confirmed to be the result of system xC − activation, as cotreatment with sulfasalazine (system xC − inhibitor) negated this rise in extracellular glutamate. These findings were reproduced in primary human myotubes but, consistent with being muscle-specific, were not observed in primary human dermal fibroblasts. To further demonstrate that statin-induced increases in ROS triggered glutamate efflux, C2C12 myotubes were cotreated with atorvastatin and various antioxidants. α-Tocopherol and cysteamine bitartrate reversed the increase in statin-induced glutamate efflux, bringing glutamate levels between 50 and 92% of control-treated levels. N-acetylcysteine (a system xC − substrate) increased glutamate efflux above statin treatment alone: up to 732% greater than control treatment. Taken together, we provide a mechanistic foundation for statin-induced myalgia and offer therapeutic insights to alleviate this particular statin-associated side-effect.
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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 | 0.001 |
| 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) | 0.002 | 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".