Dynamic Fibro-adipogenic Progenitor States Contribute to Loss of Muscle Quality After Injury in Humans

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Anterior cruciate ligament (ACL) tears are common knee injuries that often result in persistent quadriceps weakness and atrophy despite rehabilitation. The mechanisms underlying this poor muscle recovery remain unclear; however, strength and physical function deficits in skeletal muscle have been associated with poor muscle quality, driven by an accumulation of intramuscular adipose tissue (IMAT) and/or fibrosis. These changes are mediated via the differentiation of a small population of progenitor cells, fibro-adipogenic progenitors (FAPs). FAPs have the potential to adopt adipogenic or fibrogenic differentiation lineages, and in their mesenchymal state are essential for muscle homeostasis. The objective of this study was to perform unbiased single nucleus transcriptomic profiling and fate assessment of quadriceps FAPs to define their behavior as it affects muscle quality during recovery following ACL injury. We hypothesized that ACL injury triggers transcriptomic and phenotypic shifts in FAPs that contribute to deficits in skeletal muscle quality. Quadriceps muscle biopsies from the healthy and ACL-injured limbs were collected from 26 young adults (18±4 years; 11M,15F) following injury. Follow-up biopsies were obtained from the injured limb one week, 1 month and 4 months after ACL reconstruction (ACLR). Samples were processed for snRNA-seq or immunohistochemistry. snRNA-seq data were analyzed using Seurat and Monocle 3 to cluster cells, construct trajectories, and identify pseudotime-dependent gene changes in FAPs. snRNA-seq analysis revealed the majority of FAPs (68.5%) adopted an adipogenic lineage one week after ACLR, increasing to 70.7% at one month. This shift in FAP transcriptome was denoted by enriched expression of adipogenic differentiation specific genes (e.g. MME, ITGA8). In contrast, the proportion of CD55 + fibrogenic FAPs declined by 18.2% at 1 week and an additional 4% at 1-month post-ACLR. Pseudobulk analysis showed significantly reduced expression of the metalloproteinase regulator TIMP2 at both 1 and 4 months, suggesting impaired extracellular matrix (ECM) remodeling. Consistently, Collagen Hybridizing Peptide (CHP) staining showed significantly reduced collagen remodeling across all post-ACLR timepoints. Interestingly, the elevated adipogenic commitment of FAPs was not accompanied by IMAT accumulation. Immunohistochemical analysis revealed a significant decrease (p< 0.01) in IMAT% in the injured limb at 4 months post-ACLR (Healthy IMAT: 2.3±1.6%, 4 Mo post ACLR IMAT: 0.7±0.8%). These findings demonstrate that ACL injury and reconstruction induce major transcriptomic reprogramming in quadriceps FAPs, favoring the adipogenic lineage and reducing fibrogenic FAP abundance, leading to diminished collagen remodeling. Although FAPs adopt an adipogenic lineage, this commitment does not meaningfully alter IMAT accumulation within the quadriceps, underscoring the need for further investigation into the distinctive FAP differentiation stages and overall behavior following ACL injury. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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