Phenotypic divergence in rotator cuff tear and volumetric muscle loss mouse models following fibroadipogenic progenitor depletion.

Abstract

Aims: Fibroadipogenic progenitors (FAPs) are a group of resident muscle stem cells capable of differentiating into fibroblasts and adipocytes, contributing to intramuscular fibrotic and fatty degeneration after injury. However, FAPs are also thought to play a crucial role in muscle regeneration by facilitating satellite cell myogenesis. Despite this dual role, the precise functions of FAPs in muscle degeneration and regeneration remain unclear. This study aimed to utilize a FAP depletion mouse model to define the role of FAPs in two distinct, clinically relevant injury models of rotator cuff tears (RCTs) and tibialis anterior (TA) volumetric muscle loss (VML).

Methods: Six PDGFRα-Cre^ERT/DTA mice were applied for fluorescence-activated cell sorting (FACS) evaluation of FAP depletion efficiency with tamoxifen induction. Then, two groups of ten PDGFRα-Cre^ERT/DTA mice and five DTA mice underwent either unilateral supraspinatus and infraspinatus tendons and suprascapular nerve transection (RCT model) or the creation of a 4 mm diameter defect in the unilateral TA (VML model). To induce FAP depletion, tamoxifen or corn oil (control) was administered daily for two weeks before surgery. Gait analysis was conducted at six weeks post-surgery to evaluate shoulder or hindlimb function. Supraspinatus or TA muscles were harvested to assess muscle atrophy and for histological analysis.

Results: FACS analysis confirmed a 50% reduction in FAPs following tamoxifen administration in PDGFRα-Cre^ERT/DTA mice. In the RCT model, FAP depletion significantly attenuated muscle atrophy and improved fibrosis, fatty infiltration (FI), and global shoulder function. Conversely, in the VML model, FAP depletion significantly decreased muscle fibrosis but had no effect on FI and functional outcomes.

Conclusion: Our results suggest that FAPs play distinct roles in muscle regeneration depending on the specific clinical context. These models can be used to further understand the different injury mechanisms and muscle-specific properties influencing FAP roles in musculoskeletal pathology.