Department of Orthopedic Surgery, School of Medicine, Keio University, Tokyo, Japan.
Laboratory of Cell and Tissue Biology, School of Medicine, Keio University, Tokyo, Japan.
Am J Sports Med. 2021 Feb;49(2):332-339. doi: 10.1177/0363546520984122. Epub 2021 Jan 11.
The infiltration of fat tissue into skeletal muscle, a condition referred to as muscle fatty infiltration or fatty degeneration, is regarded as an irreversible event that significantly compromises the motor function of skeletal muscle.
To investigate the effect of retinoic acid receptor (RAR) agonists in suppressing the adipogenic differentiation of fibroadipogenic progenitors (FAPs) in vitro and fatty infiltration after rotator cuff tear in mice.
Controlled laboratory study.
FAPs isolated from mouse skeletal muscle were cultured in adipogenic differentiation medium in the presence or absence of an RAR agonist. At the end of cell culture, adipogenic differentiation was evaluated by gene expression analysis and oil red O staining. A mouse model of fatty infiltration-which includes the resection of the rotator cuff, removal of the humeral head, and denervation the supraspinatus muscle-was used to induce fatty infiltration in the supraspinatus muscle. The mice were orally or intramuscularly administered with an RAR agonist after the surgery. Muscle fatty infiltration was evaluated by histology and gene expression analysis.
RAR agonists effectively inhibited the adipogenic differentiation of FAPs in vitro. Oral and intramuscular administration of RAR agonists suppressed the development of muscle fatty infiltration in the mice after rotator cuff tear. In accordance, we found a significant decrease in the number of intramuscular fat cells and suppressed expression in adipogenic markers. RAR agonists also increased the expression of the transcripts for collagens; however, an accumulation of collagenous tissues was not histologically evident in the present model.
Muscle fatty infiltration can be alleviated by RAR agonists through suppressing the adipogenic differentiation of FAPs. The results also suggest that RAR agonists are potential therapeutic agents for treating patients who are at risk of developing muscle fatty infiltration. The consequence of the increased expression of collagen transcripts by RAR agonists needs to be clarified.
RAR agonists can be used to prevent the development of muscle fatty infiltration after rotator cuff tear. Nevertheless, further studies are mandatory in a large animal model to examine the safety and efficacy of intramuscular injection of RAR agonists.
脂肪组织浸润骨骼肌，这种情况被称为肌肉脂肪浸润或脂肪变性，被认为是一种不可逆的事件，会显著损害骨骼肌的运动功能。
研究维 A 酸受体（RAR）激动剂在体外抑制纤维脂肪祖细胞（FAP）成脂分化以及抑制小鼠肩袖撕裂后脂肪浸润的作用。
对照实验室研究。
从鼠骨骼肌中分离出 FAP，在存在或不存在 RAR 激动剂的情况下，在成脂分化培养基中培养。细胞培养结束时，通过基因表达分析和油红 O 染色评估成脂分化。采用肩袖切除、肱骨头去除和冈上肌去神经支配的小鼠模型，诱导冈上肌脂肪浸润。手术后，通过口服或肌肉内给予 RAR 激动剂。通过组织学和基因表达分析评估肌肉脂肪浸润。
RAR 激动剂可有效抑制 FAP 的体外成脂分化。口服和肌肉内给予 RAR 激动剂可抑制肩袖撕裂后小鼠肌肉脂肪浸润的发展。相应地，我们发现肌肉内脂肪细胞数量减少，脂肪生成标志物表达受到抑制。RAR 激动剂还增加了胶原蛋白转录物的表达；然而，在本模型中，组织学上没有胶原组织的积累。
通过抑制 FAP 的成脂分化，RAR 激动剂可减轻肌肉脂肪浸润。结果还表明，RAR 激动剂可能是治疗有发生肌肉脂肪浸润风险的患者的潜在治疗药物。RAR 激动剂增加胶原蛋白转录物表达的后果需要进一步阐明。
RAR 激动剂可用于预防肩袖撕裂后肌肉脂肪浸润的发生。然而，在大型动物模型中，仍需要进一步研究以检查 RAR 激动剂肌肉内注射的安全性和有效性。
