Preoperative systemic inflammation and muscle fatty infiltration are prognostic factors for quadriceps atrophy following anterior cruciate ligament reconstruction

Abstract

Background: Muscle atrophy following anterior cruciate ligament reconstruction (ACLR) significantly impedes functional recovery, yet its underlying prognostic factors and potential cellular mechanisms remain poorly understood.

Methods: In a cohort of 26 ACLR patients, a correlation analysis was conducted between clinical characteristics and postoperative changes in quadriceps circumference. Single-cell RNA sequencing was performed to analyze cell composition and intercellular communication in immobilized muscle. Ligand-receptor interactions were investigated using CellChat, and ferroptosis level was evaluated in fibro/adipogenic progenitors (FAPs). In vitro experiments were conducted using apoptotic muscle satellite cells (MuSCs) conditioning medium to evaluate its effects on FAP activation and adipogenic differentiation.

Results: Preoperative muscle fat infiltration (MFI), C-reactive protein (CRP) level, and concurrent meniscus repair were independent predictors of quadriceps atrophy at 3 months post-ACLR. Single-cell analysis revealed increased proportions of MuSCs and FAPs in immobilized muscle with enhanced cross-talk. Conditioned medium from apoptotic MuSCs promoted FAP viability and adipogenic ability. Moreover, ferroptosis was suppressed in FAPs under immobilization, with several regulatory genes aberrantly regulated. Mechanistically, immobilization induced a coordinated shift in the ferroptosis regulatory network within FAPs, characterized by downregulation of pro-ferroptotic genes and upregulation of anti-ferroptotic genes.

Conclusion: Preoperative MFI and systemic inflammation are risk factors for quadriceps atrophy after ACLR. Apoptotic MuSCs may promote fat infiltration by activating FAPs through suppression of ferroptosis. These findings highlight potential therapeutic targets for mitigating muscle degeneration and improving recovery outcomes after ACLR.

Keywords: anterior cruciate ligament reconstruction; apoptosis; fibro/adipogenic progenitors; inflammation; meniscus repair; muscle atrophy; muscle fatty infiltration.