Abstracts for the 36th Human Genetics Society of Australasia Annual Scientific Meeting Canberra, Australia July 22–25, 2012
Bibliographic record
Abstract
We have recently demonstrated that activation of the AMPK/PGC1 axis, the major pathway controlling mitochondriogenesis, improves the clinical and biochemical features of COX-defective recombinant mouse models of mitochondrial myopathy. In particular, we showed that AICAR, an AMPK agonist, is effective in increasing OXPHOS activities in the skeletal muscle of three mouse models of COX deficiency, including a constitutive Surf1 knockout, a musclespecific COX15 knockout, and a Sco2 knockout/knockin (KO/KI) mouse. Notably, in the Sco2 KO/KI mouse model, increased mitochondrial biogenesis was accompanied by normalization of motor endurance. We have now expanded this strategy by treating our Sco2 KO/KI mice with a set of potentially mitochondriogenic drugs including (i) metformin, another AMPK agonist that is widely used as an antidiabetic drug; (ii) nicotinamide riboside, a precursor of NAD+, which in turn activates the PGC1- agonist Sirtuin1, and (iii) resveratrol, a natural polyphenol compound, which activates PGC1- via inhibition of phosphodiesterase 4. We analyzed motor performance and COX activity in the muscle of treated vs. untreated mice. All three treatments significantly increased the motor performance of our COX-defective Sco2 KO/KI mice over four weeks, and nicotinamide riboside significantly increased also COX activity in skeletal muscle. Transcriptomic analysis is underway to further elucidate the molecular mechanisms underpinning the remarkable recovery of motor performance and biochemical proficiency of these treatments in our mitochondrial disease models. Importantly, these results can serve as a proof of principle evidence for the development of rational therapies on patients with mitochondrial (encephalo)myopathy in the near future.
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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 | 0.004 | 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 | 0.001 | 0.002 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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".