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Decoding the transcriptome of muscular dystrophy due to Ptrf deficiency using single-nucleus RNA sequencing
Xiaokai Li1, Zhining Zhong1, Ruowei Zhang1
1Livestock and Poultry Multi-omics Key Laboratory of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China.
Summary
Polymerase I and transcript release factor (PTRF) deficiency causes muscular dystrophy. Single-nucleus RNA sequencing revealed altered gene expression and metabolic pathways in muscle fibers and adipocytes, offering insights into disease mechanisms.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Polymerase I and transcript release factor (PTRF) is crucial for caveolae formation.
- PTRF deficiency leads to secondary caveolin loss and muscular dystrophy.
- Transcriptome responses in skeletal muscle subtypes during PTRF-deficient muscular dystrophy are largely unexplored.
Purpose of the Study:
- To investigate the transcriptional landscape of skeletal muscle at single-nucleus resolution in a mouse model of PTRF-deficient muscular dystrophy.
- To identify specific changes in different muscle fiber types and associated cells.
- To elucidate molecular pathways affected by PTRF deficiency.
Main Methods:
- Creation of a Ptrf knockout mouse model for muscular dystrophy.
- Application of single-nucleus RNA sequencing (snRNA-seq) on skeletal muscle.
- Bioinformatic analysis including nucleus classification, trajectory analysis, functional enrichment, metabolic pathway analysis, and gene regulatory network analysis.
Main Results:
- 11,613 muscle nuclei were classified into 12 clusters representing 11 nuclear types.
- Trajectory analysis suggested transitions between type IIb_1 and IIb_2 myonuclei.
- Ptrf knockout induced apoptotic signaling, altered receptor signaling, impacted muscle structure development, and affected the PI3K-AKT pathway.
- Overall metabolic activity decreased in myonuclei, particularly in type IIb_1.
- Mef2c, Mef2d, Myf5, and Pax3 regulon activity increased in type II myonuclei.
- Adipocytes showed enhanced lipid metabolic capacity.
Conclusions:
- Ptrf deficiency profoundly alters skeletal muscle transcriptome, affecting specific myonuclei subtypes and metabolic pathways.
- The study provides a high-resolution molecular map of muscular dystrophy induced by Ptrf deficiency.
- Findings offer insights into the complex cellular and molecular mechanisms underlying this condition and identify potential therapeutic targets.
