Fragmentation and roles of junctophilin1 in muscle of patients with cytosolic leak of stored calcium
Bibliographic record
Abstract
The mechanisms that link the primary increase in SR Ca2+ leak of MH susceptibility and related conditions to their disease phenotypes are not well understood. We found that abnormal Ca2+ homeostasis in MHS individuals induces proteolysis of junctophilin1 (JPh1), an essential structural protein of EC coupling (Perni, in 2017). Guo (in 2018) and Lahiri (in 2020) reported similar fragmentation of JPh2 in stressed hearts. Western blot of patients’ muscle with domain-specific antibodies showed a deficit of full-length JPh1 and excess of a 44-kD C-terminal fragment (JPh44) in MHS subjects. While JPh1 was located in T-SR junctions, JPh44 was found anywhere within the I band, and at high densities within nuclei—a location forbidden for JPh1. Expression and cleavage in mice of a JPh1 plasmid tagged at both ends showed that its N-terminal fragment remained in triads, and the C-terminal fragment, orthologue to JPh44, entered nuclei, which indicates that JPh44 is the C-terminal cleavage product. Endogenous calpain1 appeared in T-SR junctions, colocalized with JPh1. On muscle extracts and primary cultures, Ca2+-activated calpain1 cleaved a 44-kD JPh1 piece, consistent with the C-terminal fragment that starts at Ser241, the highest probability cleavage site found by calpain1 algorithms. Completing the identification of Ser241 as the likely start of JPh44, the tagged deletion plasmid GFP-JPh1_Δ1-240, expressed in mice, copied the location and migration of JPh44. Expression of GFP-JPh1_Δ1-240 in C2C12 myoblasts reduced by more than twofold the transcription of PI3K-Akt genes that inhibit muscle uptake and storage of glucose, including GSK3β, an inhibitor of glycogen synthase that is activated in MHS patients. In agreement with the genetic profile, GSK3β protein content decreased upon expression of GFP-JPh1_Δ1-240. In sum, the identified gene control roles of JPh44 oppose the deleterious effects of chronically elevated cytosolic [Ca2+], including late-onset hyperglycemia and type-2 diabetes (Tammineni, in 2020).
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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 | 0.000 |
| 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".