Abstract：
Lacking PTRF (polymerase I and transcript release factor), an essential caveolae component, causes a secondary deficiency of caveolins resulting in muscular dystrophy. The transcriptome responses of different types of muscle fibers and mononuclear cells in skeletal muscle to muscular dystrophy caused by Ptrf deletion have not been explored. Here, we created muscular dystrophy mice by Ptrf knockout and applied single-nucleus RNA sequencing (snRNA-seq) to unveil the transcriptional changes of the skeletal muscle at single-nucleus resolution. 11 613 muscle nuclei (WT, 5838; Ptrf KO, 5775) were classified into 12 clusters corresponding to 11 nuclear types. Trajectory analysis revealed the potential transition between type IIb_1 and IIb_2 myonuclei upon muscular dystrophy. Functional enrichment analysis indicated that apoptotic signaling and enzyme-linked receptor protein signaling pathway were significantly enriched in type IIb_1 and IIb_2 myonuclei of Ptrf KO, respectively. The muscle structure development and the PI3K-AKT signaling pathway were significantly enriched in type IIa and IIx myonuclei of Ptrf KO. Meanwhile, metabolic pathway analysis showed a decrease in overall metabolic pathway activity of myonuclei subtypes upon muscular dystrophy, with the most decrease in type IIb_1 myonuclei. Gene regulatory network analysis found that the activity of Mef2c, Mef2d, Myf5, and Pax3 regulons was enhanced in type II myonuclei of Ptrf KO, especially in type IIb_2 myonuclei. In addition, we investigated the transcriptome changes in adipocytes and found that muscular dystrophy enhanced the lipid metabolic capacity of adipocytes. Our findings provide a valuable resource for exploring the molecular mechanism of muscular dystrophy due to Ptrf deficiency.
摘要：
缺乏PTRF（聚合酶I和转录物释放因子），一个重要的洞穴成分，导致继发性小窝蛋白缺乏，导致肌营养不良。尚未探索骨骼肌中不同类型的肌纤维和单核细胞对Ptrf缺失引起的肌营养不良的转录组反应。这里,我们通过Ptrf敲除创建了肌营养不良小鼠,并应用单核RNA测序(snRNA-seq)以单核分辨率揭示了骨骼肌的转录变化.11613肌核（WT，5838;PtrfKO，5775）分为12个簇，对应11种核类型。轨迹分析揭示了肌营养不良时IIb_1型和IIb_2型肌核之间的潜在转变。功能富集分析表明，PtrfKO的IIb_1和IIb_2型肌核中凋亡信号和酶联受体蛋白信号通路显著富集，分别。PtrfKO的IIa型和IIx型肌核中肌肉结构发育和PI3K-AKT信号通路显著富集。同时,代谢途径分析显示肌核亚型在肌营养不良后的总体代谢途径活性降低，IIb_1型肌核减少最多。基因调控网络分析发现,Mef2c的活性,Mef2d,Myf5和Pax3调节子在PtrfKO的II型肌核中增强，尤其是在IIb_2型肌核中。此外,我们研究了脂肪细胞的转录组变化，发现肌营养不良增强了脂肪细胞的脂质代谢能力。我们的发现为探索Ptrf缺乏引起肌营养不良的分子机制提供了宝贵的资源。
