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 to cartilage. We also provide clinical evidence of elevated senescent cell burden in 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.