The mitochondrial‐targeted antioxidant SkQ1 prevents skeletal muscle mitochondrial‐apoptotic but not necroptotic signalling during ovarian cancer
Bibliographic record
Abstract
Abstract The degree to which mitochondrial‐linked programmed cell death pathways contribute to skeletal muscle atrophy during cancer remains unknown. Here we combined a novel and robust mouse model of metastatic ovarian cancer with chronic administration of the mitochondrial‐targeted antioxidant SkQ1 to determine the time‐dependent and muscle‐specific relationships of mitochondrial‐linked apoptotic and necroptotic signalling to the development of muscle atrophy in the type IIB‐rich gastrocnemius. Early‐stage ovarian cancer reduced type IIB fibre cross‐sectional area in the gastrocnemius but did not alter mitochondrial H 2 O 2 emission despite increased activities of mitochondrial‐linked caspase‐9 and ‐3 regulators of apoptosis. During late‐stage ovarian cancer sustained atrophy was associated with increased mitochondrial H 2 O 2 emission potential in vitro , a greater probability of calcium‐triggered mitochondrial permeability transition and increases in downstream caspase‐9 and ‐3 activities. SkQ1 attenuated mitochondrial H 2 O 2 emission and caspase‐9 and ‐3 activities in late‐stage ovarian cancer but did not prevent atrophy. Necroptosis markers were heterogeneous across time with total RIPK1 increasing during early‐stage cancer, which reverted to normal levels by late stages, whereas phosphorylated RIPK3 decreased below control levels. These discoveries indicate that preventing increases in mitochondrial‐linked apoptotic caspase‐9 and ‐3 activities during late‐stage ovarian cancer with SkQ1 does not prevent atrophy of type II B fibres. Furthermore necroptotic markers are inconclusive during cancer in this muscle type but are not modified by SkQ1. These results do not support a causal relationship between mitochondrial H 2 O 2 ‐linked apoptotic or necroptotic signalling and atrophy in type IIB fibres during ovarian cancer but do not rule out potential relationships in other muscle types. image Key points Cancer increases mitochondrial reactive oxygen species (ROS) in skeletal muscle during atrophy, but the role of ROS in regulating cell death remains unknown. We show that attenuating gastrocnemius mitochondrial ROS with the mitochondrial‐targeted antioxidant SkQ1 prevented mitochondrial‐linked pro‐apoptotic caspase 9‐ and ‐3 activities but did not affect markers of necroptosis in a mouse model of ovarian cancer. Reductions in gastrocnemius muscle fibre cross‐sectional areas and the wet weights of several muscles were not prevented by SkQ1. These findings demonstrate that mitochondrial ROS regulate apoptotic caspases but not necroptotic proteins, and neither pathway is linked to gastrocnemius atrophy in mice with ovarian cancer. The degree to which mitochondrial ROS‐linked cell death pathways regulate muscle mass in other muscle types and cancer models requires further investigation.
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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 | 0.000 |
| 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 | 0.001 |
| 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".