Muscle‐specific AMPK β1β2‐null mice display a myopathy due to loss of capillary density in nonpostural muscles
Bibliographic record
Abstract
ABSTRACT AMP‐activated protein kinase (AMPK) is a master regulator of metabolism. While Muscle‐specific AMPK β1β2 double‐knockout (β1β2M‐KO) mice display alterations in metabolic and mitochondrial capacity, their severe exercise intolerance suggested a secondary contributor to the observed phenotype. We find that tibialis anterior (TA), but not soleus, muscles of sedentary β1β2M‐KO mice display a significant myopathy (decreased myofiber areas, increased split and necrotic myofibers, and increased centrally nucleated myofibers. A mitochondrial‐ and fiber‐type‐specific etiology to the myopathy was ruled out. However, β1β2M‐KO TA muscles displayed significant ( P <0.05) increases in platelet aggregation and apoptosis within myofibers and surrounding interstitium ( P <0.05). These changes correlated with a 45% decrease in capillary density ( P <0.05). We hypothesized that the β1β2M‐KO myopathy in resting muscle resulted from impaired AMPK‐nNOSμ signaling, causing increased platelet aggregation, impaired vasodilation, and, ultimately, ischemic injury. Consistent with this hypothesis, AMPK‐specific phosphorylation (Ser1446) of nNOSμ was decreased in β1β2M‐KO compared to wild‐type (WT) mice. The AMPK‐nNOSμ relationship was further demonstrated by administration of 5‐aminoimidazole‐4‐carboxamide 1‐β‐D‐ribofuranoside (AICAR) to β1β2‐MKO muscles and C2C12 myotubes. AICAR significantly increased nNOSμ phosphorylation and nitric oxide production ( P <0.05) within minutes of administration in WT muscles and C2C12 myotubes but not in β1β2M‐KO muscles. These findings highlight the importance of the AMPK‐nNOSμ pathway in resting skeletal muscle.—Thomas, M. M., Wang, D. C., D'Souza, D. M., Krause, M. P., Layne, A. S., Criswell, D. S., O'Neill, H. M., Connor, M. K., Anderson, J. E., Kemp, B. E., Steinberg, G. R., and Hawke, T. J. Musclespecific AMPK β1β2‐null mice display a myopathy due to loss of capillary density in nonpostural muscles. FASEB J . 28, 2098–2107 (2014). www.fasebj.org
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".