Parkin overexpression attenuates muscle atrophy and rescues mitochondrial morphology in sepsis‐induced skeletal muscle dysfunction
Bibliographic record
Abstract
Rationale The accumulation of mitochondrial dysfunction is believed to contribute to skeletal muscle weakness and loss in severe sepsis. Changes in mitochondrial mitophagy, dynamics and morphology can greatly impact mitochondrial function, and vice versa. However, whether mitochondrial mitophagy, dynamics and morphology in skeletal muscle are altered in sepsis remain largely unexplored. Here, we aimed to (1) investigate the effects of sepsis on mitochondrial dynamics and morphology in skeletal muscle; and (2) evaluate the impact of parkin overexpression, a protein in charge of the removal of dysfunctional mitochondria, on muscle fiber size and mitochondrial morphology using a quantitative 2‐dimensional transmission electron microscopy approach. Methods Parkin was overexpressed for 4 weeks in the gastrocnemius (GAS) muscles of 4 week‐old mice using intramuscular injections of Adeno‐Associated Viruses (AAV). A control AAV, containing a sequence coding for the green fluorescent protein (GFP), was injected in the contralateral leg. Sepsis was induced by cecal ligation and perforation (CLP). Control (Sham) mice were subjected to the same surgery, but the cecum was neither ligated nor punctured. The impact of sepsis and Parkin overexpression on muscle myofiber size, mitochondrial morphology and gene expression were investigated. Results As expected, CLP resulted in a significant decrease in body weight 48 hours after surgery. Sepsis increased the expression of MuRF1 and Atrogen‐1, suggesting increased protein degradation. In line with these findings, CLP mice displayed an increased abundance of small fibers, a clear sign of atrophy. Parkin overexpression attenuated myofiber atrophy in CLP mice and resulted in myofiber hypertrophy in Sham mice. Septic muscle displayed enlarged and more complex InterMyoFribriallar (IMF) mitochondria. Interestingly, Parkin overexpression reduced the morphological complexity of IMF mitochondria in both Sham and CLP mice. Sepsis decreased the expression of TFAM, complex II and complex IV, while Parkin‐overexpressing muscles were protected. Sepsis increased the expression and content of LC3‐II, SQSTM1 and BNIP3. Parkin overexpression did not affect the expression and content of these proteins. Conclusions The present study shows that sepsis alters mitochondrial morphology in skeletal muscles, an effect attenuated by Parkin overexpression. Our results also indicate that Parkin overexpression attenuates sepsis‐induced myofiber atrophy. Although further studies are required, our findings place Parkin as a potential therapeutic target to counter sepsis‐induced muscle dysfunction. Support or Funding Information This study is funded by CIHR grants. GG salary support is provided by a FQRS Chercheur Boursier Junior 1 Award . JPLG is supported by a CIHR Vanier Doctoral 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) | 0.001 | 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) | 0.001 | 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".