Muscle‐specific ERRγ activation mitigates muscle atrophy after ACL injury

Anterior cruciate ligament (ACL) injury adversely affects skeletal muscle, leading to muscle atrophy and weakness, significantly impacting clinical outcomes. This study aimed to determine if estrogen-related receptor gamma (ERRγ) overexpression in skeletal muscle could mitigate muscle atrophy after ACL injury. An animal model with selective overexpression of ERRγ in skeletal muscle (ERR-gamma transgenic mice, TG) and WT control mice were used for this study. All the mice received a mechanical ACL rupture and were euthanized at 4- and 8-week post-injury. Muscle histology, atrophy, and function were evaluated and compared between the TG and WT mice. Muscle-specific ERRγ activation in TG mice demonstrated a reduction in muscle fiber atrophy, which consequently ameliorated muscle function loss post-ACL rupture. Less fibrogenic cellular expansion and muscle fibrosis were observed after ACL injury in TG mice compared to WT mice. Both male and female TG mice can maintain their muscle function 4 weeks after ACL rupture with the muscle function of female TG mice declining 8 weeks post-injury. In vivo results revealed that ERRγ activation decreased fibrogenic factors, P65, and myostatin expression, prevented the functional loss of muscle progenitor cells (MPCs), and increased CD31 and VEGF expression. These results suggest that overexpression ERRγ in skeletal muscle has a beneficial effect in preventing muscle atrophy and fibrosis after ACL rupture. This study's results will help to develop a novel rehabilitation approach that can significantly improve outcomes after ACL injury.