Inhibition of UPR <sup>ER</sup> Does Not Impair Signaling to Mitochondrial Biogenesis During Chronic Contractile Activity
Bibliographic record
Abstract
Cellular stresses that perturb the protein folding environment can be detrimental to cell health and may provoke apoptosis. In order to combat these stresses, the cell is equipped with compartment‐specific mechanisms to help regain homeostasis: the mitochondrial (UPR mt ) and endoplasmic reticulum (UPR ER ) unfolded protein responses. Acute exercise is capable of eliciting the UPR, however the role of the UPR in chronic exercise‐induced adaptations is still unclear. Exercise training can be modeled by direct stimulation (6V, 10Hz; 3hrs/day) of the peroneal nerve in Sprague Dawley rats to induce chronic contractile activity (CCA) for 7 days. We can model endurance training in one hindlimb, while the other serves as an internal control. Previously, we have shown that UPR ER signaling is upregulated during the early phases of CCA, as shown by 1.5–4 fold increases in BiP, CHOP and XBP1 spliced mRNA. We then sought to investigate the role of the UPR ER in mitochondrial adaptations by inhibiting UPR signaling with tauroursodeoxycholic acid (TUDCA). TUDCA treatment during 7 days of CCA attenuated CHOP activation by 63%, suggesting effective impairment of UPR ER signaling. Despite this, mitochondrial biogenesis (MB) was not reduced by TUDCA treatment during CCA, evidenced by comparable 22–24% increases in COX activity, a measure of mitochondrial content, after 7 days of CCA. Since the vast majority of proteins that are required for MB are nuclear‐encoded and require import into the organelle, this could imply an important role for protein import in UPR mt function. Tim23, a major translocase of the inner membrane, increased by an average of 23% as early as 1 day of CCA, suggesting a greater potential for the transport of nuclear‐transcribed proteins into the matrix. If protein import into the matrix is increased, this could be accompanied by a greater protein folding/handling capacity. Using this CCA model we can further investigate the role of protein import and its relationship with the UPR mt in potentially mediating mitochondrial adaptations to chronic exercise. Support or Funding Information Supported by NSERC.
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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 | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".