The human AMPKγ3 R225W mutation does neither enhance basal AMPKγ3-associated activity nor glycogen in human or mouse skeletal muscle
Bibliographic record
Abstract
Abstract Background AMP-activated protein kinase (AMPK) is activated during cellular energy perturbation. AMPK is composed of three subunits and several variants of AMPK complexes are expressed in skeletal muscle. The regulatory AMPKγ3 subunit is predominantly expressed in fast-twitch muscle fibers. A human AMPKγ3 R225W mutation has been described in two families. In cultured cells derived from R225W carrier muscle, the mutation was reported to increase total AMPK activity. In addition, elevated glycogen levels were observed in skeletal muscle. This led to the idea of AMPKγ3 being involved in glycogen levels in skeletal muscle. Evidence for such a causative link has never been provided. Results We studied newly obtained muscle biopsies from three human carriers of the AMPKγ3 R225W mutation and matched controls and we developed a novel knock-in mouse model carrying the AMPKγ3 R225W mutation (KI HOM). In all three human pairs, the basal AMPKγ3-associated activity was reduced when assayed in the absence of exogenous AMP. No difference was observed when assayed under AMP saturation, which was supported by findings in muscle of KI HOM mice. Furthermore, the well-established stimulatory effects of AICAR/muscle contraction on AMPKγ3-associated activity were absent in muscle from KI HOM mice. Muscle glycogen levels were not affected by the mutation in human carriers or in KI HOM mice. Conclusions The AMPKγ3 R225W mutation does not impact AMPK-associated activity in mature human skeletal muscle and the mutation is not linked to glycogen accumulation. The R225W mutation ablates AMPKγ3-associated activation by AICAR/muscle contractions, presumably through loss of nucleotide binding.
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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) | 0.000 | 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 | 0.001 | 0.000 |
| 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".