Skeletal muscle adaptations to chronic exercise in a pre-clinical model of myotonic dystrophy type 1
Bibliographic record
Abstract
Myotonic dystrophy type 1 (DM1) is the second most common muscular dystrophy and most prevalent adult form. A microsatellite expansion comprised of CTG repetitions in the dystrophia myotonica protein kinase (DMPK) gene, DM1 is characterized by muscle weakness, wasting, and myotonia. The expanded nucleotide sequence of the DMPK mRNA results in the misregulation of important RNA-binding proteins (RNABPs), Muscleblind-like 1 (MBNL1) in particular. MBNL1 becomes trapped in myonuclei within the repeating CUG transcript, which reduces the RNABPs ability to process newly synthesized mRNAs that are important for the maintenance of healthy muscle function. Recent studies with DM1 participants demonstrate that exercise is safe, enjoyable, and elicits benefits in muscle strength and function. However, the molecular mechanisms of exercise adaptation in DM1 are largely unknown. Understanding the cellular processes that drive exercise-induced remodelling may assist in the discovery of effective lifestyle interventions to mitigate DM1. In this thesis, three groups of mice were utilized: i) sedentary DM1 animals (SED-DM1), ii) DM1 mice who volitionally exercised daily on a home cage running wheel (EX-DM1), and iii) sedentary healthy, wild-type mice (WT). EX-DM1 animals ran 5.6 km/day during the 7-week experimental time course, a volume of volitional physical activity that is lower than that observed in WT animals. Post-exercise functional tests demonstrated that chronic exercise significantly improved motor performance, muscle strength and endurance. Electromyography revealed that chronic exercise mitigated myotonia. At the cellular and molecular levels, we found that chronic physical activity attenuated RNA toxicity, liberated MBNL1 from myonuclear sequestration, and selectively normalized the spliceopathy of bridging integrator 1 and muscle-specific chloride channel mRNAs. Collectively, our data indicate that chronic exercise improves DM1 at the molecular, cellular and physiological levels.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".