The couplonopathies: A comparative approach to a class of diseases of skeletal and cardiac muscle
Bibliographic record
Abstract
A novel category of diseases of striated muscle is proposed, the couplonopathies, as those that affect components of the couplon and thereby alter its operation. Couplons are the functional units of intracellular calcium release in excitation-contraction coupling. They comprise dihydropyridine receptors, ryanodine receptors (Ca2+ release channels), and a growing list of ancillary proteins whose alteration may lead to disease. Within a generally similar plan, the couplons of skeletal and cardiac muscle show, in a few places, marked structural divergence associated with critical differences in the mechanisms whereby they fulfill their signaling role. Most important among these are the presence of a mechanical or allosteric communication between voltage sensors and Ca2+ release channels, exclusive to the skeletal couplon, and the smaller capacity of the Ca stores in cardiac muscle, which results in greater swings of store concentration during physiological function. Consideration of these structural and functional differences affords insights into the pathogenesis of several couplonopathies. The exclusive mechanical connection of the skeletal couplon explains differences in pathogenesis between malignant hyperthermia (MH) and catecholaminergic polymorphic ventricular tachycardia (CPVT), conditions most commonly caused by mutations in homologous regions of the skeletal and cardiac Ca(2+) release channels. Based on mechanistic considerations applicable to both couplons, we identify the plasmalemma as a site of secondary modifications, typically an increase in store-operated calcium entry, that are relevant in MH pathogenesis. Similar considerations help explain the different consequences that mutations in triadin and calsequestrin have in these two tissues. As more information is gathered on the composition of cardiac and skeletal couplons, this comparative and mechanistic approach to couplonopathies should be useful to understand pathogenesis, clarify diagnosis, and propose tissue-specific drug development.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.005 | 0.002 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.002 | 0.003 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 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".