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Muscle stem cell renewal suppressed by Gas1 can be reversed by GDNF in mice.
Nature Metabolism ( IF 20.8 ) Pub Date : 2019-09-30 , DOI: 10.1038/s42255-019-0110-3
Liangji Li 1, 2 , Michelle Rozo 1, 2 , Sibiao Yue 1, 2 , Xiaobin Zheng 2 , Frederick J Tan 2 , Christoph Lepper 3 , Chen-Ming Fan 1, 2
Affiliation  

Muscle undergoes progressive weakening and regenerative dysfunction with age due in part to the functional decline of skeletal muscle stem cells (MuSCs). MuSCs are heterogeneous but whether their gene expression changes with age and the implication of such changes are unclear. Here we show that in mice, Growth arrest-specific gene 1 (Gas1) is expressed in a small subset of young MuSCs with its expression progressively increasing in larger fractions of MuSCs later in life. Over-expression of Gas1 in young MuSCs and inactivation of Gas1 in aged MuSCs support that Gas1 reduces the quiescence and self-renewal capacity of MuSCs. Gas1 reduces Ret signaling, which is required for MuSC quiescence and self-renewal. Indeed, we show that the Ret ligand, Glial Cell-Derived Neurotrophic Factor (GDNF), can counteract Gas1 by stimulating Ret signaling and enhancing MuSC self-renewal and regeneration, thus improving muscle function. We propose that strategies aimed to target this pathway can be exploited to improve the regenerative decline of muscle stem cells.

中文翻译:

Gas1抑制的肌肉干细胞更新可以被GDNF逆转。

随着年龄的增长,肌肉会经历进行性的衰弱和再生功能障碍,部分原因是骨骼肌干细胞(MuSCs)的功能下降。MuSCs是异质的,但尚不清楚其基因表达是否随年龄变化以及这种变化的含义。在这里,我们显示在小鼠中,生长停滞特异性基因1(Gas1)在年轻的MuSC的一小部分中表达,并且其表达在以后的较大比例的MuSC中逐渐增加。年轻的MuSC中Gas1的过度表达和衰老的MuSC中Gas1的失活支持Gas1降低MuSC的静态和自我更新能力。Gas1减少了Ret信号传递,这是MuSC静态和自我更新所必需的。实际上,我们证明了Ret配体神经胶质细胞衍生的神经营养因子(GDNF),可以通过刺激Ret信号和增强MuSC的自我更新和再生来抵消Gas1,从而改善肌肉功能。我们建议可以利用针对这一途径的策略来改善肌肉干细胞的再生衰退。
更新日期:2019-09-30
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