Metformin mitigates muscle senescent cell burden and is associated with enhanced recovery of muscle size and strength following anterior cruciate ligament tear in mice

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Injuries to the anterior cruciate ligament (ACL) are associated with protracted quadriceps muscle atrophy and weakness that may be linked to muscle-intrinsic inflammation and cellular senescence. Recent work has identified metformin as having senotherapeutic properties. The objective of this study was to investigate the ability of Metformin to mitigate quadriceps cellular senescence, atrophy, and weakness following ACL injury. We hypothesized that Metformin would decrease muscle-intrinsic inflammation and mitigate quadriceps cellular senescence, quadriceps atrophy, and quadriceps torque in mice following ACL injury. Female C57BL6/J mice (12 weeks of age) were used in all experiments. Mice underwent pre-injury quadriceps strength testing, and mice were randomized to treatment arms balanced for bodyweight-normalized quadriceps torque. Surgical transection of the ACL (ACLT) was performed on a single limb in all mice with the contralateral limb serving as an internal healthy control. Following ACLT, mice were provided Metformin (350mg/kg in the drinking water) or water-only vehicle. At 14 days following ACLT, terminal strength measures were obtained and bilateral quadriceps muscles were processed for immunohistochemistry. We observed significantly lower senescent cell burden in injured leg of the Metformin group compared to vehicle when assessing senescence associated-β-galactosidase+ (SA-β-gal+) cells (Metformin: 2.8±0.6 SA-β-gal+ cells/mm2; Vehicle: 4.7±0.9 SA-β-gal+ cells/mm2, respectively; p< 0.05) and p21+ cells (Metformin: 7.8±6.9 p21+ cells/mm2; Vehicle: 19.2±16.4 p21+ cells/mm2, respectively; p< 0.05). This was associated with an attenuation of muscle fiber atrophy (Metformin: 1.1±16.2%; Vehicle: -16.9±10.8%, p< 0.05), and a trend for greater quadriceps strength (Metformin: 1.2±0.3mNm/g; Vehicle: 0.9±0.3mNm/g, p=0.08). Staining with Sirius Red showed lower collagen percent area in the Metformin group (4.6±2.7%) compared to vehicle (11.4±4.7%, p< 0.05) in the ACLT-injured limb. These findings suggest that Metformin treatment following ACL injury may improve functional recovery by limiting the senescent cell burden within the quadriceps muscle, offering evidence for a novel and safe therapeutic strategy. Funding: This work was supported by NIH awards R01AR072061 and R01AR083375. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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