Nix induced mitochondrial fission, mitophagy, and myocyte insulin resistance are abrogated by PKA phosphorylation
Bibliographic record
Abstract
Lipotoxicity is a form of cellular stress caused by the accumulation of lipids resulting in mitochondrial dysfunction and insulin resistance in muscle. Previously, we demonstrated that Nix is a lipotoxicity‐responsive gene that accumulates in response to diacylglycerols induced by high‐fat and sucrose (HFS) feeding and exacerbated by exposure to gestational diabetes (GDM) during fetal development. Genetic inhibition of stimulus‐activated autophagy results in impaired exercise tolerance and reduced glucose uptake, yet reducing excessive mitophagy improves insulin resistance following high‐fat feeding. To provide a better understanding of these observations, we undertook a gene expression array and shot‐gun metabolomics in soleus muscle from rodents on an HFS diet and/or exposed to GDM. Interestingly, we observed a modest reduction in several autophagy‐related genes including Beclin‐1, ATG3, ‐5, and ‐7. Moreover, we observed an alteration in the ratio of cardiolipin to phosphatidic acid and reduced mitofusin‐2 expression, suggesting aberrant mitochondrial dynamics underlies muscle insulin resistance. In a series of gain‐of‐function and loss‐of‐function experiments in rodent and human myotubes, we demonstrate that Nix accumulation triggers mitochondrial depolarization, fragmentation, calcium‐dependent activation of DRP‐1, and mitophagy. In addition, Nix‐induced mitophagy leads to myotube insulin resistance through activation of mTOR‐S6K inhibition of IRS‐1. Finally, we demonstrate that Nix‐induced mitophagy and insulin resistance can be reversed by direct phosphorylation of Nix by PKA, leading to the translocation of Nix from the mitochondria and sarcoplasmic reticulum to the cytosol. These findings provide insight into the role of Nix‐induced mitophagy and muscle insulin resistance during an overfed state when overall autophagy‐related gene expression is reduced. Furthermore, our data suggests a mechanism by which exercise or pharmacological activation of PKA may overcome insulin resistance. Support or Funding Information Support by NSERC, DREAM‐CHRIM, and Research Manitoba. 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 | 0.001 |
| 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".