Endothelial FoxO Proteins Regulate Obesity Associated Skeletal Muscle Capillary Rarefaction
Bibliographic record
Abstract
Obesity is associated with skeletal muscle capillary rarefaction, which affects muscle function and whole body metabolism. Endothelial forkhead box O (FoxO) transcription factors restrain skeletal muscle angiogenesis in response to chronic endurance exercise and during ischemic recovery. We hypothesized that FoxO proteins contribute to obesity‐related capillary rarefaction. Three PolyI:C injections were administered to induce an endothelial directed FoxO1/3a/4deletion in Mx1‐Cre + ;FoxO1/3a/4 L/L mice (FoxO Δ ) but not in control Mx1‐Cre ‐ ;FoxO1/3a/4 L/L littermates (FoxO L/L ). After 16 weeks on a high‐fat (HF) or normal chow (NC) diet, protein levels of FoxO1 (HF: 1.2±0.1 vs. NC: 0.8±0.1) but not FoxO3a (HF: 0.8±0.1 vs. NC: 0.6±0.1) were elevated in the gastrocnemius muscle. HF feeding correlated with a decreased capillary‐to‐fiber ratio in FoxO L/L (NC: 2.0±0.04 vs. HF: 1.8±0.03) but not FoxO Δ mice (NC: 2.1±0.07 vs. HF: 2.1±0.05). HF fed FoxO Δ mice gained significantly less weight compared to FoxO L/L mice (11.7±1.0 vs. 17.2±1.2 g). Insulin sensitivity was improved in HF fed FoxO Δ compared to FoxO L/L mice (plasma glucose AUC during insulin tolerance test: 23.6±2.1 vs. 37.5±5.8). Analysis of existing GEO datasets from NC and HF mouse muscle established ontology enrichment of angiogenesis‐related pathways among genes that correlated inversely with FoxO1 expression. Thesefactors, putatively repressed by FoxO1, are postulated to be differentially expressed in FoxO Δ and FoxO L/L mice. These results suggest that endothelial FoxO proteins contribute to obesity related skeletal muscle capillary rarefaction, and the associated metabolic phenotypes of weight gain and impaired insulin sensitivity. Funded by CIHR.
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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) | 0.002 | 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".