Decoding the Gene Regulatory Network of Muscle Stem Cells in Mouse Duchenne Muscular Dystrophy: Revelations from Single-Nuclei RNA Sequencing Analysis.

ABSTRACT

The gene dystrophin is responsible for Duchenne muscular dystrophy (DMD), a grave X-linked recessive ailment that results in respiratory and cardiac failure. As the expression of dystrophin in muscle stem cells (MuSCs) is a topic of debate, there exists a limited understanding of its influence on the gene network of MuSCs. This study was conducted with the objective of investigating the effects of dystrophin on the regulatory network of genes in MuSCs. To comprehend the function of dystrophin in MuSCs from DMD, this investigation employed single-nuclei RNA sequencing (snRNA-seq) to appraise the transcriptomic profile of MuSCs obtained from the skeletal muscles of dystrophin mutant mice (DMDmut) and wild-type control mice. The study revealed that the dystrophin mutation caused the disruption of several long non-coding RNAs (lncRNAs), leading to the inhibition of MEG3 and NEAT1 and the upregulation of GM48099, GM19951, and GM15564. The Gene Ontology (GO) enrichment analysis of biological processes (BP) indicated that the dystrophin mutation activated the cell adhesion pathway in MuSCs, inhibited the circulatory system process, and affected the regulation of binding. The study also revealed that the metabolic pathway activity of MuSCs was altered. The metabolic activities of oxidative phosphorylation (OXPHOS) and glycolysis were elevated in MuSCs from DMDmut. In summary, this research offers novel insights into the disrupted gene regulatory program in MuSCs due to dystrophin mutation at the single-cell level.