Skeletal Muscle Dysfunction in Idiopathic Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Despite improvements in survival with disease-targeted therapies, the majority of patients with pulmonary arterial hypertension (PAH) have persistent exercise intolerance that results from impaired cardiac function and skeletal muscle dysfunction. Our intent was to understand the molecular mechanisms mediating skeletal muscle dysfunction in PAH. A total of 12 patients with PAH and 10 matched control subjects were assessed. Patients with PAH demonstrated diminished exercise capacity (lower oxygen uptake max, lower anaerobic threshold and higher minute ventilation/CO2) compared with control subjects. Quadriceps muscle cross-sectional area was significantly smaller in patients with PAH. The vastus lateralis muscle was biopsied to enable muscle fiber morphometric assessment and to determine expression levels/activation of proteins regulating (1) muscle mass, (2) mitochondria biogenesis and shaping machinery, and (3) excitation-contraction coupling. Patients with PAH demonstrated a decreased type I/type II muscle fiber ratio, with a smaller cross-sectional area in the type I fibers. Diminished AKT and p70S6 kinase phosphorylation, with increased atrogin-1 and muscle RING-finger protein-1 transcript levels, were evident in the PAH muscle, suggesting engagement of cellular signaling networks stimulating ubiquitin-proteasome-mediated proteolysis of muscle, with concurrent depression of networks mediating muscle hypertrophy. Although there were no differences in expression/activation of proteins associated with mitochondrial biogenesis or fission (MTCO2 [cytochrome C oxidase subunit II]/succinate dehydrogenase flavoprotein subunit A, mitochondrial transcription factor A, nuclear respiratory factor-1/dynamin-related protein 1 phosphorylation), protein levels of a positive regulator of mitochondrial fusion, Mitofusin2, were significantly lower in patients with PAH. Patients with PAH demonstrated increased phosphorylation of ryanodine receptor 1 receptors, suggesting that altered sarcoplasmic reticulum Ca(++) sequestration may impair excitation-contraction coupling in the PAH muscle. These data suggest that muscle dysfunction in PAH results from a combination of muscle atrophy and intrinsically impaired contractility.
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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) | 0.000 | 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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".