β3肾上腺素受体激动剂对小鼠肩袖延迟修复后肌肉脂肪浸润的治疗作用及机制研究

Fatty infiltration (FI) is a degenerative feature of rotator cuff muscles after rotator cuff tear, but FI persists and is associated with functional outcome even after successful surgical repair. However, there is no effective treatment to cure rotator cuff FI. In this study, a mouse model of delayed repair after rotator cuff tear was used to simulate patients after chronic rotator cuff tear repair. The purposes are listed as below. First, we aim to demonstrate that fibro-adipogenic progenitors (FAPs) are the main cell source of rotator cuff FI, and FAPs possess brown/beige adipose tissue (BAT) differentiation ability in this mouse model. Second, we plan to evaluate the effects of beta-3 adrenergic receptor (AR) agonist on rotator cuff muscle FI, muscular atrophy and limb function in this model. Third, we design to study the mechanism of β3AR agonists for improving fat infiltration by activating BAT in this mouse model. We hypothesize that FAPs are the cell source of rotator cuff FI and possess the ability to differentiate into BAT in this mouse model. In addition, β3AR agonist can improve rotator cuff FI, muscle atrophy and limb function in this mouse model. Last, β3AR agonist improves the FI of the rotator cuff muscle in this model by activating the FAPs differentiated BAT via the uncoupled protein-1 dependent cAMP/PKA signaling pathway. This study may provide a new therapeutic strategy for rotator cuff muscle FI in patients after chronic rotator cuff tear repair.

脂肪浸润（FI）是肩袖撕裂后肩袖肌的退变表现，但即使在成功的手术修复后，FI会依然存在并与功能预后相关。但目前尚无方法可治疗肩袖肌的FI。本课题拟使用肩袖离断后延迟修复的小鼠模型模拟慢性肩袖撕裂修复术后患者，并研究①成纤维-脂肪前体细胞（FAP）与该模型肩袖肌FI的关系及FAP向棕色/米色脂肪组织（BAT）的分化能力；②β3肾上腺素受体（AR）激动剂改善该模型肩袖肌FI的作用，并评估其对肌肉萎缩和肢体功能的影响；③β3AR激动剂通过激活BAT改善该模型肩袖肌FI的机制。我们推测FAP是该模型肩袖肌FI的细胞来源且具有向BAT的分化能力；同时，β3AR激动剂可以改善该模型肩袖肌FI、肌肉萎缩和肢体功能；并且，β3AR激动剂是通过解偶联蛋白-1依赖的cAMP/PKA信号通路激活FAPs分化的BAT从而改善该模型肩袖肌的FI。本研究或可为慢性肩袖撕裂修复术后患者肩袖肌的FI提供新的治疗策略。

脂肪浸润（FI）是肩袖撕裂后肩袖肌肉常见的退变表现，但即使在成功的手术修复后，FI会依然存在并与功能预后相关。目前尚无方法可治疗肩袖肌的FI。本课题通过使用肩袖离断后延迟修复的小鼠模型模拟慢性肩袖撕裂修复术后患者，并进行了一下研究：①通过条件性转基因小鼠证实了成纤维-脂肪前体细胞（FAP）是肩袖肌中FI的主要细胞来源，而且FAP可以向棕色/米色脂肪组织（BAT）分化；②β3肾上腺素受体激动剂（Amibegron）可明显改善肩袖肌FI和肌肉萎缩，并且还对小鼠肢体功能有显著改善效果；③Amibegron是通过UCP-1依赖的信号通路激活BAT从而改善该小鼠模型肩袖肌的FI。本研究中使用的Amibegron目前在临床试验阶段，如果可运用于临床患者，则该项目为慢性肩袖撕裂修复术后患者肩袖肌的FI提供良好的研究基础。