HUWE1 in Skeletal Muscle Prevents Muscle Fatigue via Maintaining Iron and Calcium Homeostasis
Bibliographic record
Abstract
Iron is critical to optimal athletic performance because of its role in energy metabolism, oxygen transport, and acid-base balance. However, the precise mechanism how skeletal muscle maintains iron homeostasis during exercise remains enigmatic. Here, it is demonstrated that the HECT-domain containing ubiquitin ligase E3 Huwe1 (also known as MULE or ARF-BP1) in skeletal muscle is suppressed upon exhausted exercise. Loss of Huwe1 in skeletal muscle restrains the exercise performance of Huwe1 conditional knockout (cKO) mice, accompanied with pronounced oxidative stress. Mechanistically, Huwe1 depletion stabilizes c-Myc protein, leading to upregulated sarcolipin (Sln) expression with inhibited SarcoEndoplasmic Reticulum Calcium ATPase (SERCA) activity, and downregulated ferroportin (Fpn, also known as Slc40a1) expression with iron overload. Silencing of c-Myc restores SERCA activity and iron export. Consistently, SERCA activator CDN1163, Sln silencing, or dietary iron restriction ameliorates the exercise performance of Huwe1 cKO mice. Of note, improved exercise performance is accompanied with diminished oxidative stress in Huwe1 cKO mice upon iron restriction. Taken together, the results unveil a key function for HUWE1 in skeletal muscle as a fundamental coordinator of iron and calcium homeostasis by regulating SERCA activity and iron metabolism. These findings reveal a regulatory pathway on controlling iron/calcium homeostasis and exercise capacity.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".