Targeting Follistatin to Enhance Muscle Recovery After Traumatic Joint Injury

The burden of anterior cruciate ligament (ACL) injuries continues to climb, corresponding with quadriceps muscle atrophy, weakness, and decrements in quality. These deficits show minimal response to current standard of care, necessitating alternative approaches to enhance muscle recovery and improve patient outcomes. Prior work from our lab has indicated muscle deficits are related to increases in myostatin, a TGF-Beta superfamily member and negative regulator of muscle size. In the current study, we sought to attenuate myostatin signaling through delivery of systemic follistatin or overexpress it in quadriceps muscle via plasmid electroporation to support recovery of muscle size and strength. Four- to eight-month-old Col1-eGFP mice underwent unilateral ACL transection (ACLT) injury. Col1-eGFP mice express enhanced green fluorescent protein under the control of the Collagen-a1(I) promoter, identifying Collagen 1-expressing cells. Mice were either randomized to subcutaneous administration of recombinant follistatin (1mg/kg) or saline with terminal strength measures and tissue collected 14d post-ACLT. An additional cohort of mice underwent randomization for electroporation of plasmids containing follistatin and mCherry or mCherry alone following ACLT. Similarly, terminal strength measures and quadriceps muscle were collected at 14d post-ACLT. Recombinant follistatin mitigated quadriceps muscle fiber atrophy (saline: 10.5±6.1%; follistatin: 3.8±8.5%; p=0.054) and showed a trend for greater quadriceps torque (saline: 0.7±0.3mNm/g; follistatin: 1.1±0.5mNm/g; p=0.082). Follistatin treatment did not mitigate the increase in GFP+ cells within the quadriceps post-ACLT. In the electroporation experiments, there was no difference in quadriceps torque with follistatin plasmid treatment. These data suggest that recombinant follistatin may improve muscle size and strength recovery following ACL injury and offer additional support for anti-myostatin therapies to support functional recovery following knee injury. 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.