Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, and School of Molecular Bioscience, Washington State University, Pullman, WA.
State key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China, 100193.
EBioMedicine. 2020 Oct;60:103020. doi: 10.1016/j.ebiom.2020.103020. Epub 2020 Sep 24.
During muscle regeneration, excessive formation of adipogenic and fibrogenic tissues, from their respective fibro/adipogenic progenitors (FAPs), impairs functional recovery. Intrinsic mechanisms controlling the proliferation and differentiation of FAPs remain largely unexplored.
Here, we investigated the role of retinoic acid (RA) signalling in regulating FAPs and the subsequent effects on muscle restoration from a cardiotoxin-induced injury. Blockage of retinoic acid receptor (RAR) signalling was achieved through dominant negative retinoic acid receptor α (RARα403) expression specific in PDGFRα+ FAPs in vivo and by BMS493 treatment in vitro. Effects of RAR-signalling on FAP cellularity and muscle regeneration were also investigated in a high-fat diet-induced obese mice model.
Supplementation of RA increased the proliferation of FAPs during the early stages of regeneration while suppressing FAP differentiation and promoting apoptosis during the remodelling stage. Loss of RAR-signalling caused ectopic adipogenic differentiation of FAPs and impaired muscle regeneration. Furthermore, obesity disrupted the cellular transition of FAPs and attenuated muscle regeneration. Supplementation of RA to obese mice not only rescued impaired muscle fibre regeneration, but also inhibited infiltration of fat and fibrotic tissues during muscle repair. These beneficial effects were abolished after blocking RAR-signalling in FAPs of obese mice.
These data suggest that RAR-signalling in FAPs is a critical therapeutic target for suppressing differentiation of FAPs and facilitating the regeneration of muscle and other tissues.
This study was supported by grants from the National Institutes of Health (R01-HD067449 and R21-AG049976) to M.D.
在肌肉再生过程中，来自其各自的纤维/脂肪祖细胞（FAP）的脂肪生成和纤维生成组织的过度形成会损害功能恢复。控制 FAP 增殖和分化的内在机制在很大程度上仍未得到探索。
在这里，我们研究了视黄酸（RA）信号在调节 FAP 及其随后对心肌毒素诱导损伤后肌肉修复的作用。体内通过在 PDGFRα+FAP 中特异性表达显性负性视黄酸受体α（RARα403）以及通过 BMS493 处理来阻断视黄酸受体（RAR）信号。还在高脂肪饮食诱导的肥胖小鼠模型中研究了 RAR 信号对 FAP 细胞数量和肌肉再生的影响。
RA 的补充在再生的早期阶段增加了 FAP 的增殖，同时抑制了 FAP 的分化并促进了重塑阶段的细胞凋亡。RAR 信号的缺失导致 FAP 的异位脂肪生成分化，并损害了肌肉再生。此外，肥胖破坏了 FAP 的细胞过渡并减弱了肌肉再生。向肥胖小鼠补充 RA 不仅挽救了受损的肌肉纤维再生，而且在肌肉修复过程中抑制了脂肪和纤维组织的浸润。在肥胖小鼠的 FAP 中阻断 RAR 信号后，这些有益作用被消除。
这些数据表明，FAP 中的 RAR 信号是抑制 FAP 分化和促进肌肉和其他组织再生的关键治疗靶点。
这项研究得到了美国国立卫生研究院（R01-HD067449 和 R21-AG049976）的资助。
