Selective Retinoic Acid Receptor γ Agonists Promote Repair of Injured Skeletal Muscle in Mouse

Retinoic acid signaling regulates several biological events, including myogenesis. We previously found that retinoic acid receptor gamma (RAR gamma) agonist blocks heterotopic ossification, a pathological bone formation that mostly occurs in the skeletal muscle. Interestingly, RAR gamma agonist also weakened deterioration of muscle architecture adjacent to the heterotopic ossification Lesion, suggesting that RAR gamma agonist may oppose skeletal muscle damage. To test this hypothesis, we generated a critical defect in the tibialis anterior muscle of 7-week-old mice with a cautery, treated them with RAR gamma agonist or vehicle corn oil, and examined the effects of RAR gamma agonist on muscle repair. The muscle defects were partially repaired with newly regenerating muscle cells, but also filled with adipose and fibrous scar tissue in both RAR gamma-treated and control groups. The fibrous or adipose area was smaller in RAR gamma agonist treated mice than in the control. In addition, muscle repair was remarkably delayed in RAR gamma-null mice in both critical defect and cardiotoxin injury models. Furthermore, we found a rapid increase in retinoid signaling in lacerated muscle, as monitored by retinoid signaling reporter mice. Together, our results indicate that endogenous RAR gamma signaling is involved in muscle repair and that selective RAR gamma agonists may be beneficial to promote repair in various types of muscle injuries.