Volitional exercise elicits physiological and molecular improvements in the severe D2.mdx mouse model of Duchenne muscular dystrophy
Bibliographic record
Abstract
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting and weakness. Prescribed moderate exercise in patients is beneficial, but concerns remain due to the vulnerability of dystrophic muscle to damage. Voluntary wheel running (VWR) is a self-regulated form of exercise that improves muscle health in the typical C57.mdx mouse model of DMD. The purpose of the current study was to investigate the impact of VWR in more severe and clinically relevant D2.mdx mice. Male D2.mdx animals were assigned to a sedentary (D2.mdx SED) or VWR group for 8-10 weeks, whereas DBA/2J wild-type mice served as healthy, sedentary controls (WT SED). Selective skeletal muscle mass and ex vivo force generation were elevated in D2.mdx animals that ran a relatively high volume (D2.mdx High VWR; 1.84 ± 0.84 km/day) compared to low-volume runners (D2.mdx Low VWR; 0.46 ± 0.31 km/day) and SED counterparts. VWR did not exacerbate the dystrophy, and instead attenuated the fibrotic profile compared to D2.mdx SED mice. A VWR-induced shift towards a more slow, oxidative phenotype was also observed. Mitochondrial respiration was reduced in D2.mdx SED animals versus WT SED mice but was partially restored following both Low and High VWR. Finally, a dose-dependent increase in the expression of mitochondrial proteins was observed following VWR, whereas markers of mitochondrial fusion were particularly elevated in D2.mdx High VWR mice. Our results indicate that VWR enhances muscle and mitochondrial biology in D2.mdx animals and further supports the therapeutic role of exercise for DMD patients. KEY POINTS: Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disorder characterized by muscle weakness and wasting. Skeletal and cardiac muscle quality is compromised in the dystrophic condition. Exercise promotes functional and molecular adaptations in healthy individuals and mild dystrophic mouse models. However, the effects of exercise in more severe and clinically relevant models of DMD require investigation. A relatively high volume of voluntary wheel running (VWR) augmented selective muscle mass and muscle function without exacerbating the dystrophic pathology in D2.mdx mice. Volitional exercise normalized dystrophic skeletal muscle mitochondrial respiration and upregulated mitochondrial content compared to sedentary counterparts. A higher dose of VWR increased organelle fusion protein expression compared to both healthy and dystrophic sedentary animals, as well as D2.mdx mice that ran lower volumes. Our results provide evidence from a severe preclinical model that volitional exercise may be a safe and efficacious lifestyle-based intervention for DMD.
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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 | 0.000 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".