Calcium sensitivity and mechanics of diaphragm muscle fibers in hypertrophic cardiomyopathy
Bibliographic record
Abstract
Rationale: There is evidence of respiratory dysfunction and diaphragm weakness in hypertrophic cardiomyopathy.However little is known about the mechanism that underlies this weakness at the muscle fiber level.Objectives: (i) To test if diaphragm weakness is present in a rabbit model of hypertrophic cardiomyopathy due to underlying R403Q mutation in the -myosin heavy chain (MHC) and (ii) to determine whether crossbridge kinetics or calcium sensitivity are responsible for this dysfunction.Hypothesis: Our hypothesis is that the R403Q mutation in -MHC is responsible for diaphragm muscle weakness caused by abnormal actin-myosin cycling kinetics and calcium dysregulation.Methods: Diaphragm muscle was dissected from rabbit with R403Q mutation and age-matched control and chemically permeabilized.Individual muscle fibers were isolated and mounted between a force transducer and a length controller, in temperature-controlled chamber.Fibers were submerged in maximal (pCa 4.5) and submaximal (pCa 4.7, 5.0, 5.2, 5.5, 5.7, 6.2, 6.5) activating solutions to elicit isometric contractions followed by a shortening-stretch protocol to measure rate of force redevelopment, a putative measurement of crossbridge kinetics.Results: Maximum isometric force of R403Q fibers (58.1 11.5 mN/mm 2 ) was only 61.3% that of WT fibers (94.8 14.2 mN/mm 2 ).The rate of force redevelopment of R403Q fibers (ktr = 3.31 0.76 s -1 ) was not significantly different from WT fibers (ktr = 1.89 0.28 s -1 ) (p=0.15).Calcium sensitivity, measured as pCa50 and Hill's slope of force plotted over pCa, was not different between R403Q (pCa50 4.39 0.87, Hill's slope 5.15 2.51) and WT (pCa50 4.98 0.35, Hill's slope 2.74 0.66) fibers (p=0.22 and p=0.97 respectively).viii Conclusions: Diaphragm fibers taken from rabbit with R403Q mutation exhibit weakness, but crossbridge kinetics and calcium sensitivity are not responsible for such dysfunction.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| 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".