Cellular senescence links muscle atrophy and posttraumatic osteoarthritis after ACL injury.

Traumatic knee injury leads to posttraumatic osteoarthritis (PTOA) and significant skeletal muscle weakness, resulting in chronic disability. The current standard of care frequently fails to prevent musculoskeletal dysfunction, underscoring the need to identify therapeutic mechanisms of PTOA. Using an established preclinical anterior cruciate ligament (ACL) transection model of PTOA and leveraging an innovative SPiDER-senescence-associated β-galactosidase stain to discern senescent cells, we investigated cellular senescence at single-cell resolution and identified anti-inflammatory macrophages as a predominant contributor to the senescent cell burden in both muscle and knee joint after injury. Clearance of senescent cells using the senolytic dasatinib and quercetin (D + Q) mitigated injury-induced muscle atrophy and cartilage degradation, with greater senescent cell clearance within muscle compared with cartilage. We also provide clinical evidence of elevated senescent cell burden in the muscle of patients following ACL injury and with PTOA, which is obstinate to standard of care, highlighting cellular senescence as a strong therapeutic target to improve functional recovery after traumatic joint injury.NEW & NOTEWORTHY Posttraumatic osteoarthritis (PTOA) and disability are consequences of ACL injury, but the cellular effectors that facilitate this process are unknown. Our findings demonstrate increased senescent macrophage burden in the muscle and knee joint in a preclinical ACL injury model, as well as in patients who predict poor muscle quality and weakness. We provide evidence that treatment with senolytics is an effective strategy to improve tissue quality and function and mitigate PTOA severity.