Yin Yang 1 Deficiency in Skeletal Muscle Stem Cell Aggravates Muscle Fibrosis in Duchenne Muscular Dystrophy Mouse by Disrupting Muscle Stem Cell/Macrophage/Fibro-adipogenic Progenitor Crosstalk [RNA-Seq]

Adult skeletal muscle stem cells (MuSCs), also known as satellite cells (SCs), are widely believed to be responsible for muscle regeneration, which is regulated by complex networks of intrinsic and extrinsic factors. Emerging evidence demonstrates extrinsic regulations from other cell types can significantly impact the regeneration process, especially in repetitive cycles of degeneration/regeneration environment. Here, we demonstrate that the transcription factor (TF) Yin Yang 1 (YY1) deletion in MuSCs of mdx mouse induces CCL5 expression by alleviating the repressive effect on 3D structural interactions on Ccl5 locus. This leads to the increased secretion of CCL5 from MuSCs to the muscle niche, which promotes the recruitment of macrophages (MPs) through the CCL5/CCR5 axis. Incremental MPs lead to continuous inflammation that promotes the survival of Fibro-adipogenic progenitors’ (FAP) through secreting elevated TGFβ1 to stimulate FAPs resisting apoptosis, resulting in aggravated dystrophic pathology manifested by exacerbated fibrosis. Inhibition of CCL5/CCR5 axis by Maraviroc injection effectively mitigates muscle dystrophy and enhances muscle performance in YY1 deletion mdx mouse. Altogether, our findings promote us to conclude that YY1 functions as a 3D structural protein to repress Ccl5 production at the transcriptional level in MuSCs, playing a critical role in orchestrating MuSC/MP/FAP crosstalk through CCL5/CCR5 and TGFβ1 signaling. Intrinsic deletion of YY1 in MuSCs disrupts the cellular interactions and leads to skewed muscle niche with aggravated muscle dystrophy upon chronic injury.