Long-term testosterone deficiency modifies myofilament and calcium-handling proteins and promotes diastolic dysfunction in the aging mouse heart
Bibliographic record
Abstract
The impact of long-term gonadectomy (GDX) on cardiac contractile function was explored in the setting of aging. Male mice were subjected to bilateral GDX or sham operation (4 wk) and investigated at 16–18 mo of age. Ventricular myocytes were field stimulated (2 Hz, 37°C). Peak Ca 2+ transients (fura 2) and contractions were similar in GDX and sham-operated mice, although Ca 2+ transients (50% decay time: 45.2 ± 2.3 vs. 55.6 ± 3.1 ms, P < 0.05) and contractions (time constant of relaxation: 39.1 ± 3.2 vs. 69.5 ± 9.3 ms, P < 0.05) were prolonged in GDX mice. Action potential duration was increased in myocytes from GDX mice, but this did not account for prolonged responses, as Ca 2+ transient decay was slow even when cells from GDX mice were voltage clamped with simulated “sham” action potentials. Western blots of proteins involved in Ca 2+ sequestration and efflux showed that Na + /Ca 2+ exchanger and sarco(endo)plasmic reticulum Ca 2+ -ATPase type 2 protein levels were unaffected, whereas phospholamban was dramatically higher in ventricles from aging GDX mice (0.24 ± 0.02 vs. 0.86 ± 0.13, P < 0.05). Myofilament Ca 2+ sensitivity at physiological Ca 2+ was similar, but phosphorylation of essential myosin light chain 1 was reduced by ≈50% in ventricles from aging GDX mice. M-mode echocardiography showed no change in systolic function (e.g., ejection fraction). Critically, pulse-wave Doppler echocardiography showed that GDX slowed isovolumic relaxation time (12.9 ± 0.9 vs. 16.9 ± 1.0 ms, P < 0.05), indicative of diastolic dysfunction. Thus, dysregulation of intracellular Ca 2+ and myofilament dysfunction contribute to deficits in contraction in hearts from testosterone-deficient aging mice. This suggests that low testosterone helps promote diastolic dysfunction in the aging heart. NEW & NOTEWORTHY The influence of long-term gonadectomy on contractile function was examined in aging male hearts. Gonadectomy slowed the decay of Ca 2+ transients and contractions in ventricular myocytes and slowed isovolumic relaxation time, demonstrating diastolic dysfunction. Underlying mechanisms included Ca 2+ dysregulation, elevated phospholamban protein levels, and hypophosphorylation of a myofilament protein, essential myosin light chain. Testosterone deficiency led to intracellular Ca 2+ dysregulation and myofilament dysfunction, which may facilitate diastolic dysfunction in the setting of aging.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".