Regular article
Musculoskeletal pathology
Selective Retinoic Acid Receptor γ Agonists Promote Repair of Injured Skeletal Muscle in Mouse

https://doi.org/10.1016/j.ajpath.2015.05.007Get rights and content
Under an Elsevier user license
open archive

Retinoic acid signaling regulates several biological events, including myogenesis. We previously found that retinoic acid receptor γ (RARγ) agonist blocks heterotopic ossification, a pathological bone formation that mostly occurs in the skeletal muscle. Interestingly, RARγ agonist also weakened deterioration of muscle architecture adjacent to the heterotopic ossification lesion, suggesting that RARγ 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 RARγ agonist or vehicle corn oil, and examined the effects of RARγ 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 RARγ-treated and control groups. The fibrous or adipose area was smaller in RARγ agonist–treated mice than in the control. In addition, muscle repair was remarkably delayed in RARγ-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 RARγ signaling is involved in muscle repair and that selective RARγ agonists may be beneficial to promote repair in various types of muscle injuries.

Cited by (0)

Supported by The Muscular Dystrophy Association grant MDA255541 and National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, grant AR056837.

Disclosures: M.I. received compensation from Clementia Pharmaceutical Company for consulting services. M.I. is one of the inventors named on a related patent application “Composition and Method for Muscle Repair and Regeneration” (application 20140303223). Thomas Jefferson University, the author's former institute, has licensed this technology to Clementia. M.I. received a share of royalty payments from Thomas Jefferson University. NRX195183 was provided by NuRx Pharmaceuticals (Irvine, CA).