Exploration of the Mitochondria as a Potential Therapeutic Target in Duchenne Muscular Dystrophy
Bibliographic record
Abstract
Duchenne muscular dystrophy (DMD) is a fatal muscle wasting condition resulting from the loss of the structural protein dystrophin. The disease is characterized by severe muscle wasting and weakness that results in early death due to cardiac and/or respiratory failure. Currently, there is no cure for DMD and current standard of care (glucocorticoid steroids) only addresses secondary pathologies, and is accompanied with a myriad of negative side effects. Previous work has established the mitochondria as a contributor to dystrophic pathology and a valid therapeutic target. \n\nThe primary focus of this thesis was to examine novel therapies that modulate metabolism in DMD, to determine if secondary pathologies, including fibrosis, atrophy, weakness and mitochondrial stress are attenuated. Additionally, we aimed consider the effects of adenylates and creatine metabolism on mitochondrial permeability transition (mtPT) in a permeabilized muscle fibre system. Our study findings reveal that ATP significantly attenuates mtPT and that both creatine and ADP should be considered in buffer composition for assessment of mtPT. \n\nNext, using the mitochondrial-enhancing compound, Olesoxime, we examined the effect of attenuating mitochondrial stress on dystrophic pathology. Unexpectedly, improvements to mitochondrial respiration and reactive oxygen species attenuation, were creatine-dependent, indicating that creatine sensitivity was preserved by Olesoxime treatment. These improvements to bioenergetics also happened in association with markers of muscle breakdown (serum creatine kinase), and improvement in muscle function (cage hand time and recovery of diaphragm force after fatigue). Finally, short-term treatment with the novel adiponectin receptor agonist, ALY688-SR, mitigated aspects of mitochondrial stress in quadriceps, diaphragm and hippocampus, while improving markers of fibrosis and muscle atrophy in the diaphragm, and recognition memory. \n\nOverall, this thesis indicates that attenuating mitochondrial stress in dystrophic muscle and brain improves markers of muscle function and quality, while preserving cognitive function and warrants longer term treatment protocols.
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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 | 0.001 | 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".