Ampk Activation Normalizes Myogenic Regulatory Gene Expression In The Skeletal Muscle Of Dystrophic Animals
Bibliographic record
Abstract
Skeletal muscle regeneration is a highly orchestrated physiological process that is dependent on the myogenic capacity of muscle stem cells (MuSCs). Recent studies have demonstrated a regulatory role for adenosine monophosphate-activated protein kinase (AMPK) in acute myotrauma-induced MuSC fate. However, the precise function of AMPK during persistent muscle regeneration has yet to be investigated. PURPOSE: To evaluate MuSC biology in response to a novel AMPK agonist in a model of cyclical skeletal muscle degeneration and regeneration. METHODS: Dystrophic C57BL/10-mdx (mdx) animals were treated with a single dose (5 mpk) of the orally bioactive AMPK activator MK-8722 via gavage and were euthanized 3-, 6-, or 12-hours (hrs) post-administration. Wild-type (WT) mice were also obtained at 3 hrs post-MK-8722 treatment. WT and mdx animals treated with the vehicle (Veh) solution served as control groups. Skeletal muscles were harvested and processed for immunoblotting, qPCR, and immunofluorescence analyses. RESULTS: As expected, gene expression of the myogenic regulators paired box 7 (Pax7), myogenic factor 5 (Myf5), myoblast determination protein (MyoD), and myogenin (MyoG) in dystrophic mice was significantly higher (~3-6-fold) relative to their WT littermates. We also observed a greater (p < 0.05) number of MyoD+ myonuclei and active MuSCs (Pax7+/MyoD+ myonuclei) in muscles of mdx animals relative to the WT group. MK-8722 administration significantly elevated AMPK and downstream acetyl-CoA carboxylase activation status in WT and dystrophic muscles. Pax7 and MyoG gene expression was 6-fold lower (p < 0.05) 6 hrs following MK-8722 administration relative to their Veh controls and similar (p > 0.05) to their WT counterparts. Furthermore, preliminary analyses (n = 4-7) revealed statistical trends toward fewer MyoD+ myonuclei and activated MuSCs in MK-8722 treated mdx animals at 12 hrs post-treatment compared to the Veh group. CONCLUSIONS: The present study is the first to evaluate MuSC biology following a single dose of a new-generation AMPK activator in dystrophic skeletal muscle. Our results suggest that acute pharmacological targeting of AMPK delays MuSC activation in highly regenerative skeletal muscle and prefaces further investigation of the therapeutic value of AMPK agonists in muscular dystrophy.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 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) | 0.003 | 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".