Modulation of Microglia by Voluntary Exercise or CSF1R Inhibition Prevents Age-Related Loss of Functional Motor Units
Modulation of Microglia by Voluntary Exercise or CSF1R Inhibition Prevents Age-Related Loss of Functional Motor Units
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DOI：
10.1016/j.celrep.2019.10.003
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发表时间：
2019-11-05
期刊：
影响因子：
8.8
通讯作者：
Nash, Mark
中科院分区：
文献类型：
--
作者：
Giorgetti, Elisa;Panesar, Moh;Nash, Mark
由运动神经元引起的骨骼肌神经支配的年龄相关性丧失会导致神经肌肉功能受损，这是一种公认的临床现象。然而，其潜在的发病机制仍不清楚。在对小鼠的研究中，我们发现，可以通过对抗衰老脊髓中的神经毒性小胶质细胞来维持运动单位(MU)的数量。我们观察到，通过运动单位数量估计(MUNE)检测到的显著神经变化发生在老年小鼠肌肉功能丧失之前。这与老年脊髓神经元重塑和小胶质细胞激活的基因表达变化相一致。自愿运动可以防止MU的丧失，并逆转小胶质细胞的激活。通过抑制CSF1R耗尽小胶质细胞也可以防止与年龄相关的MUNE下降和神经肌肉连接中断，这意味着两者之间存在因果联系。我们的结果表明，脊髓小胶质细胞的增龄性变化有助于老年小鼠神经肌肉功能的下降，并表明去除老化的神经毒性小胶质细胞可以防止或逆转MU的丢失。
Age-related loss of skeletal muscle innervation by motor neurons leads to impaired neuromuscular function and is a well-established clinical phenomenon. However, the underlying pathogenesis remains unclear. Studying mice, we find that the number of motor units (MUs) can be maintained by counteracting neurotoxic microglia in the aged spinal cord. We observe that marked innervation changes, detected by motor unit number estimation (MUNE), occur prior to loss of muscle function in aged mice. This coincides with gene expression changes indicative of neuronal remodeling and microglial activation in aged spinal cord. Voluntary exercise prevents loss of MUs and reverses microglia activation. Depleting microglia by CSF1R inhibition also prevents the age-related decline in MUNE and neuromuscular junction disruption, implying a causal link. Our results suggest that age-related changes in spinal cord microglia contribute to neuromuscular decline in aged mice and demonstrate that removal of aged neurotoxic microglia can prevent or reverse MU loss.