Muscle atrophy after ACL reconstruction involves molecular mechanisms beyond unloading

Anterior cruciate ligament reconstruction (ACLR) leads to profound muscle atrophy and weakness that remain resistant to rehabilitation. Although early recovery typically involves a brief period of limb unloading, the degree to which disuse alone accounts for muscle pathology after ACLR remains unclear. Here, we leveraged publicly available RNA-seq datasets of muscle biopsies from vastus lateralis obtained 7 days after ACLR or 10 days after unilateral lower limb suspension (ULLS), each with matched control limbs, to directly compare disuse-driven and ACLR-specific early transcriptional responses. Despite similar periods of reduced loading, substantial transcriptomic divergence was identified using both intersection and interaction bioinformatic analyses. Only 16% of differentially expressed genes (DEGs) were common to both ACLR and ULLS, with ACLR eliciting over 1,000 more DEGs than ULLS. ACLR was characterized by reduced extracellular matrix (ECM) remodeling and robust induction of denervation-responsive genes, which were not observed with unloading alone. These findings indicate that unloading contributes only modestly to the early muscle transcriptomic response following ACLR. Identifying potential ACLR-specific molecular effectors of atrophy advances our understanding of its unique pathophysiology that may underlie poorer functional recovery.NEW & NOTEWORTHY Disuse is often suggested as a major driver of quadriceps pathology following anterior cruciate ligament reconstruction (ACLR). This study identifies shared and unique gene signatures that occur early with ACLR and unilateral lower limb suspension (ULLS), highlighting ACLR-specific responses that likely contribute to prolonged quadriceps atrophy and weakness.