Single Cell RNA Sequencing Of Regenerating Skeletal Muscle Reveals A Senescence Response Which Is Necessary For Optimal Muscle Repair
Bibliographic record
Abstract
Satellite cells drive skeletal muscle regeneration, a process regulated by factors released into the local muscle environment; however the source of this trophic support is poorly defined. In this regard, recent work has identified a supportive role for cells commonly associated with aging and pathology, termed “senescent cells”. The PURPOSE of this study was to determine the function of cellular senescence in normal skeletal muscle repair in rodents. METHODS: The tibialis anterior (TA) of C57BL6 mice was injured with cardiotoxin (CTX) and collected across a time-course. To examine senescent cell function during muscle repair, mice where treated with the senolytic compound (ABT-263) to selectively ablate senescent cells. RESULTS: The number of senescent cells (SA-β-gal+ cells) rapidly increased following injury (p <0.05) which returned to baseline by 21 days post-CTX. SA-β-gal+ cells displayed other markers consistent with senescence such as a lack of proliferation (EDU-) and the presence of DNA damage (γH2AX). qPCR analysis of putative senescence pathways including p16, p21 and p53 as well as factors commonly secreted by senescent cells were significantly upregulated in CTX-injected muscle in comparison to uninjured muscle (p <0.05). To identify the cell types which become senescent, single-cell RNA sequencing (scRNAseq) was performed on 5-day post CTX skeletal muscle which revealed that fibrogenic-adipogenic progenitors (FAPs), endothelial cells and macrophages demonstrated increased expression of the senescence markers Glb1, CDKN1A and Trp53 while no satellite cells become senescent. These findings were confirmed in vivo through IHC analysis of SA-β-gal and marker specific analysis of FAPs (PDGFRα), endothelial cells (CD31) and macrophages (F4/80). Importantly, senolytic treatment during regenerative myogenesis in vivo reduced the number of SA-β-gal+ cells by 44% which coincided with significant reductions in muscle fibre cross-sectional area (25%) and the number of nuclei/fibre (12%). CONCLUSION: A transient wave of cellular senescence contributes to endogenous muscle repair to influence muscle fibre size following injury.
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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 | 0.001 |
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".