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Fibrotic Differentiation Proile of Skeletal and Cardiac Muscle Fibroadipogenic Progenitors in D2-mdx Mouse

ABSTRACT: Muscle fibrosis is a key pathological feature of Duchenne muscular dystrophy (DMD) and is closely associated with disease progression. Fibroadipogenic progenitors (FAPs) are major contributors to fibrosis, yet the precise mechanisms remain unclear. To investigate FAP dynamics and lineage specification, we generated dual-reporter mice (PRURD2) by crossing D2.B10-Dmdmdx/J (D2-mdx) mice with FAP and brown/beige adipose tissue (BAT) reporter lines. Corresponding control mice (PRURDBA) were established on the DBA/2J background. At 12 months, heart, diaphragm, and tibialis anterior (TA) muscles were collected for histological analysis. FAPs were isolated via FACS and subjected to single-cell RNA sequencing. PRURD2 mice exhibited increased fibrosis across all muscles compared to controls (p < 0.01) and a significant rise in PDGFRα-GFP+ FAPs (p < 0.05). UMAP clustering identified 11 distinct FAP subpopulations, with the fibrosis-associated CD55 cluster enriched in PRURD2 mice. Pseudotime analysis showed lineage progression from progenitor clusters toward the fibrogenic CD55 cluster. CellChat analysis indicated increased interactions in PRURD2 mice involving fibrosis-related pathways like COLLAGEN, TGF-β, WNT, NOTCH, and ANGPTL. Additionally, fibrosis-related signaling pathways such as THY1, TWEAK, EPHA, EPHB, and SEMA6 showed increased interactions among FAP clusters in PRURD2 mice. Differential gene expression analysis revealed top upregulated genes including Cxcl13, Cxcl3, Ly6d, Klk1, Fgf23, Serpinb2, Mmp13, Ccl17, Postn, and Adam12. PRURD2 mice develop severe fibrosis in skeletal and cardiac muscle, driven by FAP-induced signaling pathways and genes. This model is valuable for understanding muscle fibrosis in DMD and developing anti-fibrotic therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE322960 | GEO | 2026/08/12

REPOSITORIES: GEO

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Project description:Repair of acutely injured skeletal muscle relies on an adequate inflammatory response predominated by monocyte/macrophage infiltration. The process requires injured muscles to produce C-C chemokine ligand 2 (CCL2). The present study identified fibro/adipogenic progenitors (FAPs) as the primary source of CCL2 in acutely injured muscle where the pro-inflammatory subcluster of FAPs expanded rapidly and expressed the highest level of CCL2. FAP-specific deletion of Ccl2 largely abolished CCL2 production by acutely injured muscle, reducing monocyte/macrophage infiltration and impairing muscle regeneration. In vitro, the CCL2 expression by both mouse and human FAPs were induced by danger signal-containing muscle homogenates through toll-like receptor signaling. The CCL2 expression by mouse FAPs was also induced by infiltrating neutrophils partly through their secretion of pro-inflammatory cytokines. Our findings suggest an important immune sentinel role for FAPs, as they sense muscle damage, produce CCL2 to recruit inflammatory MOs, and promote injury repair.progression of dystrophic muscle in Duchenne muscular dystrophy (DMD) patients and DMD mouse model mdx5cv mice. The cellular and molecular mechanism underlying this difference has yet to be fully elucidated. To this end, the present study compared the single-cell transcriptomes of intramuscular monocytes/macrophages from uninjured and acutely injured quadriceps of 14 weeks-old wild-typed (WT) mice, and from quadriceps and diaphragm of age-matched mdx5cv mice, using single cell-based RNA sequencing (scRNA-seq) analysis. Our results identified multiple functionally diverse monocyte/macrophage clusters co-existing in each injured muscle sample. Both Ly6Chi and Ly6Clo intramuscular monocytes/macrophages were heterogenous, containing different clusters among different injury conditions. These clusters did not conform to strict M1/M2 activation, and were involved differentially in inflammation, extracellular matrix (ECM) remodeling, and myogenesis during skeletal muscle injury repair. These findings uncovered the heterogeneity of monocyte/macrophage activation in both acutely injured and dystrophic skeletal muscle, shedding light on the molecular and cellular mechanisms underlying the differential roles of monocytes/macrophages in acute skeletal muscle injury and muscular dystrophy in DMD.

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Fibrotic Differentiation Proile of Skeletal and Cardiac Muscle Fibroadipogenic Progenitors in D2-mdx Mouse

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