THE POTENTIAL OF CONTRACTILE ACTIVITY TO REVERSE THE SEVERITY OF MTDNA DEFECTS
Bibliographic record
Abstract
Defects in mitochondrial DNA (mtDNA) evoke adaptive responses in the nuclear genome, leading to altered mitochondrial biogenesis. PURPOSE To examine adaptations in the protein import machinery, and transcription factors involved in mitochondrial biogenesis. METHODS We used immunoblotting and biochemical techniques to evaluate protein levels and protein import in C2C12 muscle cells depleted of mtDNA (rho- cells), as well as in fibroblasts from a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). RESULTS In rho- cells, Tom20, Tom34 and Tim23 protein levels were reduced by 25%, 12% and 59% of control, respectively. No change was observed in HSP60, but mtHSP70 was induced by 2-fold in rho-, relative to control cells. These changes were accompanied by a 21% increase in import into the mitochondrial matrix in rho-cells (p < 0.05). In contrast, in MELAS cells mtHSP70 was elevated by 70% while Tom20 and Tom34 protein levels were increased by 45% and 112%, respectively, while HSP60 was reduced by 25%. Matrix protein import was not impaired in MELAS cells. Overexpression of Tom34 in C2C12 cells resulted in a 13% (p < 0.05) increase in import into the matrix. To evaluate the effect of contractile activity, we stimulated C2C12 myotubes for 4 days. A 67% (p < 0.05) increase in Tom34 was observed. In rho- cells, NRF-1 and Tfam protein levels declined by 33% and 54%, respectively, while no change was observed in PGC-1. Rho- cells had a lower rate of oxygen consumption (VO2) and reduced ATP, along with a 2-fold increase in lactate (p < 0.05). In contrast, in stimulated cells, 42% and 78% increases were observed in mtDNA and VO2, respectively (p < 0.05). CONCLUSION Our findings suggest that in response to mtDNA defects, compensatory adaptations occur in the mitochondrial import pathway to maintain a normal rate of import. These data support a role for exercise in reducing the pathological phenotype associated with mtDNA depletion. Supported by CIHR.
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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) | 0.000 | 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) | 0.001 | 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 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".