Selective Retinoic Acid Receptor γ Agonists Promote Repair of Injured Skeletal Muscle in Mouse
Selective Retinoic Acid Receptor γ Agonists Promote Repair of Injured Skeletal Muscle in Mouse
复制标题
DOI：
10.1016/j.ajpath.2015.05.007
复制
发表时间：
2015-09-01
影响因子：
6
通讯作者：
Iwamoto, Masahiro
中科院分区：
文献类型：
--
作者：
Di Rocco, Agnese;Uchibe, Kenta;Iwamoto, Masahiro
视黄酸信号调节几种生物学事件，包括肌生成。我们以前发现，视黄酸受体γ（RAR γ）激动剂阻断异位骨化，一种主要发生在骨骼肌中的病理性骨形成。有趣的是，RAR γ激动剂也减弱了异位骨化病变附近肌肉结构的恶化，表明RAR γ激动剂可能对抗骨骼肌损伤。为了验证这一假设，我们用烧灼法在7周龄小鼠的胫骨前肌中产生了严重缺陷，用RAR γ激动剂或载体玉米油处理它们，并检查RAR γ激动剂对肌肉修复的影响。在RAR γ治疗组和对照组中，肌肉缺损部分由新再生的肌肉细胞修复，但也充满了脂肪和纤维瘢痕组织。RAR γ激动剂处理的小鼠的纤维或脂肪面积小于对照组。此外，在严重缺陷和心脏毒素损伤模型中，RAR γ缺失小鼠的肌肉修复显著延迟。此外，我们发现在撕裂的肌肉中类维生素A信号的快速增加，如通过类维生素A信号报告小鼠所监测的。总之，我们的研究结果表明，内源性RAR γ信号参与肌肉修复，选择性RAR γ激动剂可能有利于促进各种类型肌肉损伤的修复。
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.