■建议将体力活动作为抑郁症的替代疗法。Myokines,在体力活动中从骨骼肌分泌,在骨骼肌-脑轴中起重要作用。Musclin,一种新发现的Myokine,发挥身体耐力,然而,肌肉对情绪行为的影响,比如抑郁症,尚未评估。本研究旨在研究肌肉素的抗抑郁作用,并阐明小鼠抑郁样行为与下丘脑神经肽之间的联系。
■我们在强迫游泳(FS)测试中测量了不动时间,在高架迷宫(EPM)测试中在开放臂中花费的时间,下丘脑神经肽的mRNA水平,并计数了室旁核(PVN)中的c-Fos阳性细胞,弓状核(ARC),腹膜内(i.p.)施用肌球蛋白的小鼠和孤核(NTS)。接下来,我们评估了选择性促肾上腺皮质激素释放因子(CRF)1型受体拮抗剂的作用,选择性CRF2型受体拮抗剂,黑皮质素受体(MCR)激动剂,和选择性黑皮质素4受体(MC4R)激动剂对肌肉组织诱导的行为变化的影响。最后,我们使用暴露于反复水浸(WI)压力的小鼠评估了肌肉素的抗抑郁作用。
■我们发现,肌球蛋白的i.p.和i.c.v.给药减少了小鼠开放臂中的不动时间和相对时间(开放%),并增加了尿皮质素2(Ucn2)水平,但降低了下丘脑中的前黑皮质素水平。c-Fos阳性细胞的数量在PVN和NTS中增加,但在腹膜内施用musclin的小鼠的ARC中减少。还发现PVN中的c-Fos阳性细胞是Ucn2阳性。CRF2型受体拮抗剂和黑皮质素4受体激动剂的集中给药阻断了肌肉的抗抑郁和焦虑作用,分别。周围施用肌球蛋白还可以预防抑郁样行为和反复WI应激引起的下丘脑Ucn2水平的降低。
■这些数据通过激活中央Ucn2信号来确定肌肉素的抗抑郁作用,并表明肌肉素和Ucn2可以成为新的治疗靶标和介导肌肉-脑轴的内源性肽。
Physical activity is recommended as an alternative treatment for depression. Myokines, which are secreted from skeletal muscles during physical activity, play an important role in the skeletal muscle-brain axis. Musclin, a newly discovered myokine, exerts physical endurance, however, the effects of musclin on emotional behaviors, such as depression, have not been evaluated. This study aimed to access the anti-depressive effect of musclin and clarify the connection between depression-like behavior and hypothalamic neuropeptides in mice.
We measured the immobility time in the forced swim (FS) test, the time spent in open arm in the elevated-plus maze (EPM) test, the mRNA levels of hypothalamic neuropeptides, and enumerated the c-Fos-positive cells in the paraventricular nucleus (PVN), arcuate nucleus (ARC), and nucleus tractus solitarii (NTS) in mice with the intraperitoneal (i.p.) administration of musclin. Next, we evaluated the effects of a selective corticotropin-releasing factor (CRF) type 1 receptor antagonist, selective CRF type 2 receptor antagonist, melanocortin receptor (MCR) agonist, and selective melanocortin 4 receptor (MC4R) agonist on changes in behaviors induced by musclin. Finally we evaluated the antidepressant effect of musclin using mice exposed to repeated water immersion (WI) stress.
We found that the i.p. and i.c.v. administration of musclin decreased the immobility time and relative time in the open arms (open %) in mice and increased urocortin 2 (Ucn 2) levels but decreased proopiomelanocortin levels in the hypothalamus. The numbers of c-Fos-positive cells were increased in the PVN and NTS but decreased in the ARC of mice with i.p. administration of musclin. The c-Fos-positive cells in the PVN were also found to be Ucn 2-positive. The antidepressant and anxiogenic effects of musclin were blocked by central administration of a CRF type 2 receptor antagonist and a melanocortin 4 receptor agonist, respectively. Peripheral administration of musclin also prevented depression-like behavior and the decrease in levels of hypothalamic Ucn 2 induced by repeated WI stress.
These data identify the antidepressant effects of musclin through the activation of central Ucn 2 signaling and suggest that musclin and Ucn 2 can be new therapeutic targets and endogenous peptides mediating the muscle-brain axis.