Circadian Regulation Of The Plasminogen Activator System In The Development Of Skeletal Muscle Fibrosis
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
PURPOSE: Skeletal muscle accounts for approximately 40% of a person’s weight and is fundamental for movement. Reductions in movement are associated with decreased quality of life and increased mortality. Therefore, adequate regeneration of skeletal muscle following injury is crucial. Remodeling, including some degradation, of the extracellular matrix (ECM) by the plasminogen activator (PA) system is essential for regeneration. This is performed by the activity of plasmin, which is converted from plasminogen via uPA and tPA. To prevent excessive ECM degradation, the PA system is regulated by plasminogen activator inhibitor-1 (PAI-1); however, skeletal muscle fibrosis can result from excessive PAI-1 activity. Another interconnected system involved in skeletal muscle regeneration is circadian rhythms. Circadian rhythms are 24-hour cycles which involve the proteins Bmal1 and Clock, and the families of Period and Cryptochrome. Notably, mice with muscle-specific loss of Bmal1 demonstrate skeletal muscle fibrosis; however, the mechanisms of this are not well characterized. Therefore, the goal of this study is to investigate the role of circadian rhythms in PA system-mediated development of skeletal muscle fibrosis. METHODS: A pilot study utilizing 18 global Bmal1-/- mice and 18 wild-type mice will be conducted to determine if disruption to the circadian rhythm alters PA system activity. Mice will be sacrificed at ZT0, ZT4, ZT8, ZT12, ZT16 and ZT20 (n = 3/group), allowing for characterization of the entire circadian cycle. Skeletal muscle samples will be homogenized and prepared for western blotting to assess Bmal1 and PAI-1 protein levels. PCR analysis of the circadian genes Bmal1, Clock, Per1, Per2, Cry1, Cry2, and Rev-erbα, and the PA system genes PAI-1, uPA, and plasminogen will be done. RESULTS: Preliminary analysis of PAI-1 levels indicate that there is expression of PAI-1 in skeletal muscle as compared to control tissue (11.22 ± 2.30 vs. 5.09 ± 2.39; data are in arbitrary units; mean ± standard deviation). CONCLUSION: This work will develop our understanding of the role of the PA system in the development of skeletal muscle fibrosis and determine if further examination of the interconnection between the PA system, skeletal muscle fibrosis, and circadian rhythms is warranted. Supported by: NSERC#2016-05073
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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 it