The Role of GSK3β in SERCA Dysfunction and the Development of Arrhythmogenic Cardiomyopathy
Bibliographic record
Abstract
The sarco(endo)plasmic reticulum Ca 2+ ‐ATPase (SERCA) pump catalyzes the active transport of Ca 2+ into the sarcoplasmic reticulum and is responsible for over 70% of Ca 2+ turnover after muscle contraction. Phospholamban (PLN) is a well‐known SERCA regulator, and impaired SERCA function due to reductions in SERCA and/or enhanced inhibitory PLN action has been linked to the development of various cardiomyopathies. Arrhythmogenic cardiomyopathy (ACM) is an inherited, non‐ischemic heart disease presenting with ventricular arrhythmias, hypo/dyskinesia, and fibrotic remodeling. Over 60% of ACM cases are caused by pathogenic variants in genes encoding the cardiac desmosome, where Desmoglein‐2 ( DSG2 ) is the second most prevalent desmosomal gene variant in the ACM patient population. Using Dsg2 mutant ( Dsg2 mut/mut ) mice, previous studies showed that the enzyme glycogen synthase kinase‐3β (GSK3β), plays a major role in ACM pathogenesis. Inhibiting GSK3β in these mice improved cardiac contractility and ACM pathological phenotypes. We have shown that GSK3β inhibition in cardiomyocytes can also improve SERCA function in wild‐type (WT) mice; however, the role of GSK3β activity on SERCA function in Dsg2 mut/mut mice is currently unknown. Here, we sought to examine the effects of GSK3β inhibition on SERCA function using a GSK3β‐specific inhibitor, SB216763 (SB2), in Dsg2 mut/mut mice. At 3 weeks of age, both WT and Dsg2 mut/mut mice were treated with SB2 (2.5 mg/kg/day) or equivalent volume/kg/day of vehicle (DMSO) for 13 weeks via intraperitoneal injection. After treatment, mice were sacrificed and hearts were collected and homogenized. Our results show that cardiomyocytes obtained from vehicle treated Dsg2 mut/mut mice had significantly lower SERCA2a expression (‐52%, p <0.01) compared to vehicle treated WT mice, leading to reduced SERCA2a:PLN (‐65%, p =0.04). Maximal SERCA activity was also significantly lower in vehicle treated Dsg2 mut/mut mice (‐65%, p =0.001). However, in myocardium from SB2 treated Dsg2 mut/mut mice, maximal SERCA activity, SERCA2a expression, and SERCA2a:PLN ratio were all restored to near WT levels. We also examined the effects of heterozygous and homozygous GSK3β S9A mutation in the Dsg2 mut/mut mice, which prevents phosphorylation and maintains GSK3β in its constitutively active form. When comparing WT with Dsg2 mut/mut heterozygous and homozygous GSK3β S9A mutants, we saw a significant but non‐progressive decrease in maximal SERCA activity (‐60%, p =0.02 and ‐58%, p =0.03 respectively). In conclusion, these results show that SERCA function is negatively impacted in Dsg2 mut/mut cardiomyocytes. Conversely, GSK3β inhibition with SB2 treatment improved SERCA content and activity to healthy WT levels. These results further illuminate the role of GSK3β in ACM pathogenesis and support the use of GSK3β inhibitors in its treatment, as our new promising results indicate this therapeutic strategy can also improve Ca 2+ handling.
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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 | 0.003 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.000 |
| 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".