Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer
Bibliographic record
Abstract
Muscle loss with cancer causes weakness, worsens quality of life, and predicts reduced overall survival rates. Recently, muscle weakness was identified during early-stage cancer before atrophy develops. This discovery indicates that mechanisms independent of muscle loss must contribute to progressive weakness. While mitochondrial stress responses are associated with early-stage ‘pre-cachexia’ weakness, a causal relationship has not been established. Here, using a mouse model of metastatic ovarian cancer cachexia, we identified that the well-established mitochondrial-targeted plastoquinone SkQ1 partially prevents muscle weakness occurring before the development of atrophy in the diaphragm. Furthermore, SkQ1 improved force production during atrophy without preventing atrophy itself in the tibialis anterior and diaphragm. These findings indicate that atrophy-independent mechanisms of muscle weakness occur in different muscle types throughout ovarian cancer. Ovarian cancer reduced flexor digitorum brevis (FDB) whole muscle force production and myoplasmic free calcium ([Ca 2+ ] i ) during contraction in intact single muscle fibers, both of which were prevented by SkQ1. Remarkably, changes in mitochondrial reactive oxygen species and pyruvate metabolism were heterogeneous across time and between muscle types which highlights a considerable complexity in the relationships between mitochondria and muscle remodeling throughout ovarian cancer. These discoveries identify that muscle weakness can occur independent of atrophy throughout ovarian cancer in a manner that is linked to improved calcium handling. The findings also demonstrate that mitochondrial-targeted therapies exert a robust effect in preserving muscle force early during ovarian cancer during the pre-atrophy period and in late stages once cachexia has become severe. • Ovarian cancer mice were treated with a mitochondrial targeting antioxidant. • Antioxidant treatment prevented pre-atrophy muscle weakness in ovarian cancer in mice. • Antioxidant treatment prevented post-atrophy weakness in two different muscles. • Antioxidant treatment effects were linked to improved calcium handling in muscle fibres. • Atrophy was not prevented, suggesting atrophy independent mechanisms of weakness.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".