Single-cell RNA Sequencing Revealed Fibro-adipogenic Progenitors As The Major Contributor To Radiation-induced Skeletal Muscle Fibrosis
Bibliographic record
Abstract
Radiation therapy causes skeletal muscle atrophy, and fibrosis in cancer survivors due to alterations in skeletal muscle mononuclear cells. However, a lack of mechanistic understanding hinders effective therapies on skeletal muscle side effects of radiation. PURPOSE: To identify transcriptional changes at the single-cell level induced by radiation and how these changes may influence cell-cell communication within skeletal muscle in a murine model of therapeutic radiation. METHODS: A fractionated radiation dose (8.2 Gray/dose) was administered for three alternating days to one hindlimb of C57Bl/6 J male mice age five weeks (IR). The rest of the body was lead-shielded, and the contralateral limb was used as a non-IR control (CON). Single-cell RNA sequencing was performed at 24 hours and 56-days post-IR. RESULTS: Transcriptomic profiling revealed 13 distinct cell populations, including muscle satellite cells (MuSCs), fibro-adipogenic progenitors (FAPs), and macrophages. A deep quiescent MuSC population expressing CD34+ was significantly reduced (p-adjusted<0.05, from 55% CON to 25% IR limb), and a subpopulation of macrophages type 2 expressing Ccr2+ was substantially increased at 56-days post-IR compared to CON (p-adjusted<0.05, from 11.19% CON to 43.06% IR limb). Genes related to fibroblast proliferation were up-regulated in FAPs at 24-hours post-IR, and a fibrotic phenotype persisted in FAPs at 56-days post-IR (Differentially expressed genes (DEGs), p-adjusted<0.05). A conserved Cdkn1a signature was observed in all cells post-IR (DEGs, p-adjusted<0.05) and inflammatory signalling mediators such as SPP1, TNF-α, and PARs were upregulated in the IR-limb at 56-days (DEGs, p-adjusted p < 0.05). Intercellular communication analysis revealed FAPs as the primary contributor of extracellular matrix and target of TGF-β signalling at both 24-hours and 56-days post-IR (DEGs, p-adjusted<0.05). CONCLUSIONS: Radiation depletes deep quiescent MuSCs, induces a conserved senescent transcriptomic profile across all muscle mononuclear cells, and increases pro-fibrotic signaling, particularly in FAPs. This work provides novel targets for reducing the long-term late effects of radiation in skeletal muscle. Natural Sciences and Engineering Research Council of Canada (RGPIN-2017-04320)
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".