Altered Skeletal Muscle Microtubule‐Mitochondrial Voltage Gated‐Dependent Anion Channel (VDAC) 2 Binding is Related to Bioenergetic Impairments after Paclitaxel but not Vinblastine Chemotherapies
Bibliographic record
Abstract
Rationale Muscle weakness in response to chemotherapy is thought to be related to mitochondrial dysfunction. However, the underlying mechanisms by which chemotherapy alters mitochondrial bioenergetics remain unknown, but are likely unique to different types of these cytotoxic compounds. Taxanes (eg. Paclitaxel) and vinka alkaloids (eg. Vinblastine) prevent cancer cell mitosis by stabilizing and destabilizing microtubules, respectively. In mature muscle fibres (ie. non‐mitotic), microtubules are thought to regulate mitochondrial bioenergetics by directly binding the ADP/ATP exchanger voltage dependent anion channel (VDAC) on the outer mitochondrial membrane. As ADP simultaneously regulates oxidative phosphorylation and oxidant generation by modulation of membrane potential, we hypothesized that manipulating microtubule architecture with paclitaxel and vinblastine would alter tubulin‐VDAC interactions and influence ADP‐dependent respiration and H 2 O 2 emission. As VDAC is thought to be involved in the formation of the mitochondrial permeability transition pore (mPTP) under calcium stress, we also hypothesized that these compounds would alter mitochondrial calcium retention capacity (CRC) required for mPTP formation. Methods : Single muscle fibres and permeabilized fibre bundles were isolated from rat extensor digitorum longus muscles and incubated in paclitaxel (2hr) and vinblastine (1hr) at 4°C prior to assessing protein‐protein interactions (proximity ligation assay) and mitochondrial bioenergetics. Results Paclitaxel increased both a‐ ( p=0.01 ) and bII‐tubulin ( p=0.01 ) interactions with VDAC2 which was associated with a decreased ability of ADP to attenuate H 2 O 2 emission (main effect, p=0.0006 ) despite no effect on ADP‐stimulated respiration or CRC. In contrast, vinblastine had no effect on the amount of a‐ and bII‐tubulin interactions with VDAC but still increased ADP‐stimulated respiration (main effect, p= 0.006 ), decreased the ability of ADP to attenuate H 2 O 2 emission (main effect, p=0.002 ) and sensitized mPTP formation as demonstrated by reduced CRC ( p=0.04 ). Conclusion and Discussion The results demonstrate that both microtubule stabilizing and destabilizing chemotherapies cause diverse mitochondrial dysfunctions which may provide insight into their detrimental effects on muscle function. Collectively, these findings partially support the tubulin‐VDAC model of regulating mitochondrial bioenergetics but suggests that microtubule architecture may also regulate mitochondrial function in mature muscle fibres through additional mechanisms. Support or Funding Information Funding was provided to C.G.R.P. by National Science and Engineering Research Council (#436138‐2013) with infrastructure supported by Canada Foundation for Innovation, Ontario Research Fund and the James H. Cummings Foundation. S.V.R was supported by Ontario Graduate Scholarship. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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) | 0.002 | 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".