Can the inhibition of glycogen synthase kinase 3 mimic the physiological effects of exercise on muscle and other organs?
Bibliographic record
Abstract
Regular exercise is widely recognized for its numerous health benefits, including enhancing overall well-being, reducing the risk of or alleviating symptoms from various chronic diseases, and slowing the aging process. Consequently, exercise extends the period of life free from long-term conditions and diseases, otherwise known as healthspan. Even with this knowledge, the proportion of the global population that meets recommended physical activity levels remains startlingly low and has consistently decreased over time. Numerous individual and socioeconomic risk factors contribute to the sedentary lifestyle, which, along with the downward trend in physical activity, underscores the need to investigate the therapeutic potential of exercise mimetics. Glycogen synthase kinase 3 (GSK3) is a constitutively active enzyme that is inhibited by regular exercise in rodents. This review discusses recent work demonstrating how GSK3 inhibition, through pharmacological or genetic manipulation, can mimic the effects of exercise, along with possible pathways of action, particularly through the increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) – a central player in already established exercise mimetics. Our review focuses on two main outcomes commonly observed with exercise mimetics: improved endurance and the exertion of anti-obesity effects, including enhanced fat loss and insulin sensitivity. Additionally, since the existing exercise mimetics largely focus on replicating aerobic exercise by facilitating skeletal muscle adaptations, we center our review on this exercise modality and tissue. However, we also explore GSK3 inhibition and its potential to mimic resistance exercise, as well as its benefits to various tissues beyond skeletal muscle, including the heart, adipose tissue, bone, and brain. Finally, we propose future directions and experiments that could place GSK3 inhibition at the forefront of exercise mimetic research.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".