Cellular senescence links muscle atrophy and posttraumatic osteoarthritis after ACL injury

Authors

• Alexander R. Keeble, University of KentuckyFollow
• Allison Owen, University of Kentucky
• Sara Gonzalez-Velez, University of Kentucky
• Nicholas T. Thomas, University of KentuckyFollow
• Camille R. Brightwell, University of KentuckyFollow
• Peyton J. Balawender, University of Kentucky
• Madeline G. O'Daniel, University of Kentucky
• Helena C. Weiss, University of Kentucky
• Haley Noehren, University of Kentucky
• Heather Thompson, University of Kentucky
• Karen Sofia Zuluaga-Osorio, University of Kentucky College of Medicine
• Zane T. Bates, University of Kentucky
• Lauren Gottlieb, University of Kentucky
• Douglas E. Long, University of KentuckyFollow
• Douglas Harrison, University of Kentucky
• Philip Kern, University of KentuckyFollow
• Caitlin E. Conley, University of KentuckyFollow
• Michael A. Samaan, University of KentuckyFollow
• Stephen Duncan, University of Kentucky
• Austin Stone, University of KentuckyFollow
• Darren Johnson, University of KentuckyFollow
• Yuan Wen, University of KentuckyFollow
• Brian Noehren, University of KentuckyFollow
• Cory Dungan, University of KentuckyFollow
• Christopher Fry, University of KentuckyFollow

Abstract

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.

Document Type

Article

Publication Date

8-1-2026

Digital Object Identifier (DOI)

10.1152/function.017.2026

Archival?

Archival

Repository Citation

Keeble, Alexander R.; Owen, Allison; Gonzalez-Velez, Sara; Thomas, Nicholas T.; Brightwell, Camille R.; Balawender, Peyton J.; O'Daniel, Madeline G.; Weiss, Helena C.; Noehren, Haley; Thompson, Heather; Zuluaga-Osorio, Karen Sofia; Bates, Zane T.; Gottlieb, Lauren; Long, Douglas E.; Harrison, Douglas; Kern, Philip; Conley, Caitlin E.; Samaan, Michael A.; Duncan, Stephen; Stone, Austin; Johnson, Darren; Wen, Yuan; Noehren, Brian; Dungan, Cory; and Fry, Christopher, "Cellular senescence links muscle atrophy and posttraumatic osteoarthritis after ACL injury" (2026). Biology Faculty Publications. 236.
https://uknowledge.uky.edu/biology_facpub/236